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| Intellectual disability - microarray and sequencing v5.307 | SRSF1 |
Achchuthan Shanmugasundram gene: SRSF1 was added gene: SRSF1 was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: SRSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SRSF1 were set to 37071997 Phenotypes for gene: SRSF1 were set to Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, OMIM:620489 Review for gene: SRSF1 was set to GREEN Added comment: There are 17 individuals from 16 different families were reported with 15 different monoallelic variants (mostly de novo) in SRSF1 gene. They were reported with a neurodevelopmental disorder mainly comprising neurological abnormalities such as intellectual disability/ developmental delay, motor delay, speech delay, and behavioural disorders and facial dysmorphisms. Intellectual disability was present in 16 of 17 individuals (3 severe, 2 moderate, 3 mild to moderate, 3 mild, 1 borderline and 4 unknown severity), while the remaining one had learning disability. Functional testing of a subset of variants in Drosophila supported pathogenicity in most, but 2 missense variants showed no functional effect and were classified VUS. This gene has already been associated with neurodevelopmental disorder in both OMIM (MIM #620489) and Gene2Phenotype ('limited' rating in the DD panel). Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.298 | MTSS1L | Arina Puzriakova Phenotypes for gene: MTSS1L were changed from Global developmental delay; Intellectual disability; Ophthalmological anomalies; Microcephaly; Mild facial dysmorphisms to Intellectual developmental disorder with ocular anomalies and distinctive facial features, OMIM:620086 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.255 | PABPC1 |
Sarah Leigh edited their review of gene: PABPC1: Added comment: PABPC1 variants have not been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35511136 reports four de novo PABPC1 variants in four unrelated cases with a phenotype of global DD, movement coordination disorders, seizures, behavioral disorders and mild facial dysmorphisms. Intellectual disability ranged in the cases from profound (1/4), IQ: 61 (1/4) and IQ: 79 (2/4). Seizures were apparent in the all of the three cases where it was assessed. Molecular modeling of the variants suggested that they would result in a reduced binding affinity to the messenger RNA metabolism-related protein - PAIP2. This predicted effect was seen in coimmunoprecipitation assays between variant PABPC1 and PAIP2 (PMID: 35511136). Further functional studies in PMID: 35511136, showed that the proliferation of neural progenitor cells in Pabpc1 knockdown mouse embryo brains were decreased, this effect was rescued by the wild-type Pabpc1, but not by the variants c.1691A>G (p.Glu564Gly) or c.1709T>C (p.Ile570Thr). Other variants were identified in 3/4 cases in PMID: 35511136, two of these had a ACMG VUS classification (RBBP4: c.845A>G, p.(Asn282Ser), IGF2R: c.1850G>A p.Cys617Tyr), while the third variant was monoallelic, whereas bialleic variants in this gene are associated with disease (KDM5B: c.2265dupA, p.(Tyr755*))(PMID: 35511136, table 1).; Changed rating: GREEN |
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| Intellectual disability - microarray and sequencing v5.209 | DAGLA |
Achchuthan Shanmugasundram changed review comment from: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ. In addition, the functional data suggests potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect (PMID:35737950).; to: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ. In addition, the functional data suggests potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect (PMID:35737950). This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype. |
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| Intellectual disability - microarray and sequencing v5.205 | DAGLA | Achchuthan Shanmugasundram changed review comment from: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ (PMID:35737950).; to: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ. In addition, the functional data suggests potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect (PMID:35737950). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.171 | TRA2B |
Achchuthan Shanmugasundram changed review comment from: This gene has already been associated with phenotypes in Gene2Phenotype (with 'moderate' rating in the DD panel), but not in OMIM. Sources: Literature; to: PMID:36549593 reported 12 individuals from 11 unrelated families identified with 11 different heterozygous variants in TRA2B gene. The variants arose de novo in 10 families, while the variant was inherited from father to son in one family. 6 variants were expected to disrupt the translation start site in exon 1 (start-loss variants), 3 were expected to disrupt the splicing process at the exon 2/3 boundary (splice-affecting variants), and the remaining 2 were expected to produce a premature stop codon (truncating variants). These patients presented with a neurodevelopmental disorder comprising developmental delay/ intellectual disability (in all patients), axial or global hypotonia (10 patients), delayed motor milestones (all patients), behavioural issues (8 patients), speech impairment (9 patients), epilepsy (7 patients, initial presentation as infantile spasms in 6 and unclassified epileptic encephalopathy in 1), brain abnormalities (10 patients) and microcephaly (5 patients). The degree of ID was severe to profound for 6 individuals, moderate to severe for 2 and mild to moderate for 3. In addition, functional studies in mice showed that heterozygous knockout mice developed normal, while complete knockout mice cannot develop embryonically. This gene has already been associated with phenotypes in Gene2Phenotype (with 'moderate' rating in the DD panel), but not in OMIM. Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.105 | SLC32A1 |
Achchuthan Shanmugasundram changed review comment from: PMID:36073542 reported four unrelated patients with four different de novo missense variants in SLC32A1 gene reported with global developmental delay, moderate-to-severe intellectual disability, infantile-onset epilepsy within the first 18 months of life, and a choreiform, dystonic, or dyskinetic movement disorder. In silico modeling and functional analyses showed that these variants can impair GABAergic neurotransmission through at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short-term plasticity. Sources: Literature; to: PMID:36073542 reported four unrelated patients with four different de novo missense variants in SLC32A1 gene reported with global developmental delay, moderate-to-severe intellectual disability, infantile-onset epilepsy within the first 18 months of life, and a choreiform, dystonic, or dyskinetic movement disorder. In silico modeling and functional analyses showed that these variants can impair GABAergic neurotransmission through at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short-term plasticity. Although this gene has not yet been associated with phenotypes in OMIM, it has been added to Gene2Phenotype with 'moderate' rating in the DD panel. Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.105 | SLC32A1 |
Achchuthan Shanmugasundram gene: SLC32A1 was added gene: SLC32A1 was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: SLC32A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SLC32A1 were set to 36073542 Phenotypes for gene: SLC32A1 were set to developmental and epileptic encephalopathy, MONDO:0100062 Review for gene: SLC32A1 was set to GREEN Added comment: PMID:36073542 reported four unrelated patients with four different de novo missense variants in SLC32A1 gene reported with global developmental delay, moderate-to-severe intellectual disability, infantile-onset epilepsy within the first 18 months of life, and a choreiform, dystonic, or dyskinetic movement disorder. In silico modeling and functional analyses showed that these variants can impair GABAergic neurotransmission through at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short-term plasticity. Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.24 | KDM5A |
Achchuthan Shanmugasundram changed review comment from: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms. PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment. In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice.; to: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms. PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment. In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice. This gene has already been associated with phenotype in Gene2Phenotype (biallelic inheritance with 'limited' rating), but not in OMIM. |
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| Intellectual disability - microarray and sequencing v5.23 | KDM5A |
Achchuthan Shanmugasundram changed review comment from: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms. PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.; to: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms. PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment. In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice. |
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| Intellectual disability - microarray and sequencing v5.19 | KDM5A |
Achchuthan Shanmugasundram changed review comment from: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms. PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech and developmental delay.; to: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms. PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment. |
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| Intellectual disability - microarray and sequencing v4.56 | ISCA-37420-Loss | Arina Puzriakova Phenotypes for Region: ISCA-37420-Loss were changed from PMID: 18628315 developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour, other clinically important features include epilepsy, heart defects and kidney/urologic anomalies; 610443; PMID: 25217958; Koolen-De Vries syndrome 610443 to Koolen-De Vries syndrome, OMIM:610443; Developmental delay/intellectual disability, hypotonia, distinctive facial features, congenital malformations, and behavioural feature | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.55 | ISCA-37420-Loss |
Arina Puzriakova commented on Region: ISCA-37420-Loss: Previously in phenotypes field: PMID: 18628315 developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour, other clinically important features include epilepsy, heart defects and kidney/urologic anomalies; 610443; PMID: 25217958; Koolen-De Vries syndrome 610443 |
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| Intellectual disability - microarray and sequencing v3.1733 | MTSS1L |
Arina Puzriakova gene: MTSS1L was added gene: MTSS1L was added to Intellectual disability. Sources: Literature new-gene-name, Q4_22_rating tags were added to gene: MTSS1L. Mode of inheritance for gene: MTSS1L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MTSS1L were set to 36067766 Phenotypes for gene: MTSS1L were set to Global developmental delay; Intellectual disability; Ophthalmological anomalies; Microcephaly; Mild facial dysmorphisms Review for gene: MTSS1L was set to GREEN Added comment: Huang et al. 2022 (PMID: 36067766) reported five unrelated individuals with the same heterozygous de novo variant (c.2011C>T; p.Arg671Trp) in MTSS2 (formally known as MTSS1L). Linkage analysis was not performed but given the variants arose de novo and the mixed ethnicity of the affected individuals (4 European, 1 Chinese) a founder effect can be ruled out. Subjects displayed a shared phenotype of GDD and/or ID, ophthalmological anomalies (most commonly nystagmus), microcephaly (primary in 2, relative in 3) and shared mild facial dysmorphisms. The single adult patient also presented with seizures and optic atrophy. Functional studies showed the variant leads to a decrease in mRNA level but does not impact protein levels of MTSS2. However, a Drosophila model demonstrated that loss of the fly ortholog results in defects in locomotor and visual functions which were rescued by human MTSS2 and only partially rescued by the MTSS2 c.2011C>T variant. Overexpression of the c.2011C>T variant caused similar phenotypes as the LoF mutant indicating a possible dominant-negative effect. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1701 | UBAP2L |
Konstantinos Varvagiannis gene: UBAP2L was added gene: UBAP2L was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: UBAP2L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: UBAP2L were set to 35977029 Phenotypes for gene: UBAP2L were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system Penetrance for gene: UBAP2L were set to unknown Review for gene: UBAP2L was set to GREEN Added comment: Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1). Details provided below. Not associated with any phenotype in OMIM, G2P or SysNDD. -------- Jia et al (2022 - PMID: 35977029) describe 12 affected individuals with heterozygous de novo pLoF variants in UBAP2L. Phenotype: Features included hypotonia, speech (11/11) and motor delay (8/12), ID (8/10 with formal evaluation), variable behavioral concerns (ADHD 5/11, ASD in 4/10, etc). Seizures were reported in 7/12 with 3/10 having a formal diagnosis of epilepsy. Few had microcephaly (3/10). Facial dysmorphisms were common (9/9) and included abnormal palpebral fissures, deep prominent concha, high broad forehead, hypertelorism, thin upper lip and mild synophrys (each in 4 or less individuals). Short stature or skeletal alterations were described in some (4/10 each). Role of the gene: UBAP2L encodes an essential regulator of stress granule assembly. Stress granules are membraneless cytoplasmic compartments in eukaryotic cells, induced upon a variety of stressors and playing a role in regulation of gene expression. Variants identified : 9 nonsense/frameshift UBAP2L variants and 3 splicing ones were reported, in all cases as de novo events, upon trio/quad exome sequencing. All were absent from gnomAD. There were no other causative variants. Variant effect/studies (NM_014847.4 / NP_055662.3) : - Minigene assays revealed that the 3 splice variants all resulted in out-of-frame exon skipping. - In patient fibroblasts one of these splice variants was demonstrated to result to reduced protein levels. - 8 of the 9 nonsense/frameshift variants were predicted to result to NMD. - 1 nonsense variant (c.88C>T/p.Q30*) was shown to result to decreased protein expression in patient fibroblasts, with detection of the protein using an antibody for the C terminus but not the N terminus. Protein N-terminal sequencing confirmed that the protein lacked the N terminus, with utilization of an alternative start site (11 codons downstream). - Generation of HeLa UBAP2L KO cell lines resulted in significant reduction of SG numbers which was also the case for 4 variants studied, under stress conditions. - The protein has a DUF domain (aa 495-526) known to mediate interaction of UBAP2L with G3BP1 (a stress granule marker) with deletions of this domain leading to shuttling of UBAP2L from the cytoplasm to the nucleus. Truncating variants upstream of the DUF domain were shown to result in nuclear localization. Mouse model : - The authors generated Ubap2l KO model with hmz deletion of Ubap2l resulting in a lethal phenotype (2.6% survived) and htz deletion leading to behavioral issues (low preference for social novelty, anxious-like behaviors) and cognitive impairment. - Ubap2l haploinsufficiency resulted in abnormal cortical development and lamination with reduction of neural progenitor proliferation. - Ubap2l deficiency was shown to impair SG assembly during cortical development both under physiological stress conditions or upon utilization of an oxidative stress inducer. Additional evidence of UBAP2L and SG overall in pathogenesis of NDDs: - Based on DNMs from 40,853 individuals with NDDs from 26 studies (9,228 with ASD, 31,625 with DD/ID) the authors demonstrate significant excess of DNM in 31 genes encoding SG components, regulators or both, the latter being the case for UBAP2L and 2 further genes (G3BP1 and G3BP2 - both with crucial roles in SG assembly). - Excess dn splice-site (N=3) and missense (N=5) variants in G3BP1 were observed in the above cohort [c.95+1G>A, c.353+1G>T, c.539+1G>A / p.S208C, R320C, V366M]. - Excess dn missense (N=7) variants in G3BP2 were observed in the above cohort [p.R13W, D151N, E158K, L209P, E399D, K408E, R438C]. - Generation of G3BP1 or G3BP2 KO HeLa cell lines and immunofluorescence upon use of oxidative stress inducer revealed significant reduction of stress granules. - Generation of HeLa cell lines for 5 G3BP1 mutants (R78C*, R132I*, S208C*, R320C*, V366M) and 7 G3BP2 mutants (p.R13W*, D151N*, E158K, L209P*, E399D, K408E, R438C) revealed that several (those in asterisk) resulted in significantly fewer SG formation under oxidative stress compared to WT while the subcellular distribution of the proteins under stress was identical to WT. - Among the identified genes for SG enriched for DNMs, CAPRIN1 was implicated in previous publications as a NDD risk gene with 3 dn missense SNVs reported (p.I373K, p.Q446H, p.L484P). CAPRIN1 binding to G3BP1/2 has been shown to promote SG formation. Significant reduction of SG was observed in CAPRIN1 KO HeLa lines. p.I373K abolished interaction with G3BP1/2 and disrupted SG formation. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1580 | DROSHA |
Konstantinos Varvagiannis gene: DROSHA was added gene: DROSHA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: DROSHA were set to 35405010 Phenotypes for gene: DROSHA were set to Global developmental delay; Intellectual disability; Seizures; Cerebral white matter atrophy; Abnormality of the corpus callosum; Abnormality of movement; Stereotypic behavior; Abnormality of head or neck; Short foot Penetrance for gene: DROSHA were set to unknown Mode of pathogenicity for gene: DROSHA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: DROSHA was set to AMBER Added comment: Profound DD, ID and seizures have been reported in 2 unrelated subjects with de novo missense variants. The gene has a role in miRNA biogenesis. Both variants described have been shown to have effect on DROSHA's function in Drosophila / C. elegans (partial loss-of-function vs possibility of antimorphic effect discussed || in gnomAD several individuals with LoF alleles / Z=3.98 – pLI : 0.09). There is currently no DROSHA-related phenotype in OMIM, G2P, SysNDD. In PanelApp Australia the gene has amber rating in genetic epilepsy and microcephaly panels (not currently included in the ID one). Consider inclusion in the current panel with amber rating. Also consider inclusion in other possibly relevant panels (given postnatal microcephaly, abn. corpus callosum, progressive white matter atrophy, etc) [ NOT added ] ----- Barish, Senturk, Schoch et al (2022 - PMID: 35405010) describe the phenotype of 2 unrelated individuals with de novo missense DROSHA variants. Features included generalized hypotonia, postnatal microcephaly (-2,6 and -6 SD), feeding difficulties, profound DD and ID, seizures, abnormal movements (choreoathetosis / stereotypic movements), variable respiratory symptoms (in one case episodes of hyperventilation/apnea), cardiovascular or skeletal findings. Brain MRI demonstrated white matter atrophy and thin corpus callosum in both. Brachycephaly with broad face as well as short feet were also among the shared features. Both were investigated by trio ES/GS which were otherwise non diagnostic and without other candidate variants. The 1st individual harbored a de novo htz missense DROSHA variant (c.3656A>G/p.Asp1219Gly) while the 2nd subject had another missense variant (c.4024C>T/p.Arg1342Trp) [NM_013235.4] confirmed by Sanger seq. DROSHA (on 5p13.3) encodes a ribonuclease, subunit of the microprocessor complex, involved in miRNA biogenesis. Specifically, miRNAs are transcribed as part of pri-miRNAs (primary-miRNAs) which are cleaved to pre-miRNAs (precursor-miRNAs) in the nucleus by DROSHA (and its partner DGCR8 or Pasha) and then exported to the cytoplasm for further processing. Cleavage of pre-miRNAs by DICER1 generates mature miRNAs subsequently loaded to the RISC (RNA-induced silencing) complex which uses miRNA as template for recognition and cleavage of complementary mRNA with RNAse. As the authors discuss, miRNA defects have a well-established role in development of model organisms e.g. (several Refs. provided): - in C. elegans miRNA mutants causing lethality, developmental arrest and heterochronicity - in Drosophila playing a role in the development of ovary, eye, nervous system etc. - in mice mRNAs play a role in BMP and TGF-beta signaling while neuronal loss of miRNA processing leads to neurodegeneration/anatomical defects. Feingold syndrome 2 is the single Mendelian disease associated to date with miRNAs, through deletion of a cluster containing 6 MIR genes. miRNA dysregulation is also observed in Rett syndrome - and DROSHA implicated in the pathogenesis of the syndrome - as MECP2 and FOXG1 are cofactors of the microprocessor complex regulating processing of miRNA. One of the individuals here reported had a clinical diagnosis of Rett spectrum while both had overlapping features with Rett s. Studies of DROSHA-dependent miRNAs in fibroblasts from one individual revealed significantly altered expression of mature miRNA (e.g. increased miR98, a miRNA with reduced expression in studies of somatic DROSHA variants) although this was not likely due to processing errors (given only a modest decrease of precursor miRNAs). Previous studies have demonstrated that drosha (the Drosophila ortholog) null mutants die during post-embryonic development with 100% lethality before adulthood (3rd instar larval stage/beginning of pupariation). Mosaic flies with mutant eyes are small-eyed, while viable hypomorphic alleles display synaptic transmission defects (several Refs provided). Here, homozygous flies for null alleles died at the end of 3rd instar larval stage/beginning of pupariation, while loss of drosha resulted in lack of imaginal disc tissue (which surrounds the larval brain) and severely reduced brain size, the latter similar to the microcephaly phenotype. [To the best of my understanding] introduction of a mutated genomic rescue construct (carrying similar substitutions as those observed in human subjects) in eye-specific drosha null (W1123X) flies was partially able to rescue eye/head size for wt or Asp1219Gly (human:Asp1084Gly) suggesting that the latter is a partial LoF allele. Arg1210Trp (corresponding to human Arg1342Trp) was able to rescue the eye phenotype and was not damaging to the function in the specific assay. Drosha expression levels were similar for genomic rescue flies either for wt or for the Asp-Gly variant suggesting that the effect was not due to expression levels (but rather function). Expression of mature miRNAs known to be regulated by Drosha were not affected when comparing wildtype larvae with genomic construct for wt or Asp1084Gly. Upon expression of human cDNA using GAL4/UAS system in drosha mutant (null) eye clones, the reference partially rescued the eye size defect, Asp-Gly behaved as partial loss-of-function allele (~50% function compared to ref), while the Arg-Trp variant was shown to behave as a weaker loss-of-function allele. The authors generated eye-specific drosha mutant clones to study the aging adult eye using ERG recordings. While null mutants display almost no response to light (7- and 20-day old flies), wt genomic rescue was shown to rescue ERG responses, Asp-Gly variant had significant defects (at both 7 and 20 days) and the Arg-Trp had defects approaching statistical significance only at the age of 20 days. Overall these data suggested that Arg-Trp had less severe effect compared to Asp-Gly (as above) while both variants led to progressive neuronal dysfunction. Using CRISPR/Cas9 the authors generated C.elegans knock-ins for a variant analogous to the Asp1219Gly human one. Homozygous animals were inviable at larval stages, displayed a heterochronic phenotype (heterochronicity : development of cells or tissues at an abnormal time relative to other unaffected events in an organism / miRNAs are known to be involved in the heterochronic gene pathway) while this variant was deleterious to the Drosha's ability to process miRNAs. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1568 | ROBO1 |
Konstantinos Varvagiannis gene: ROBO1 was added gene: ROBO1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ROBO1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: ROBO1 were set to 35348658; 35227688; 34193621; 31448886; 30692597; 29194579; 28592524; 28402530; 28286008 Phenotypes for gene: ROBO1 were set to ROBO1-related NDD Penetrance for gene: ROBO1 were set to unknown Review for gene: ROBO1 was set to AMBER Added comment: DD/ID has been reported in some individuals with biallelic (e.g. 4 subjects in the study by Münch et al, 1 additional case reported by Calloni et al) or monoallelic ROBO1 variants (e.g. P2 in the study by Huang et al, with a diagnosis of EOEE due to a neomorphic variant). Consider amber rating pending further review. ------ Huang et al (2022 - PMID: 35348658) Monoallelic & Biallelic Novel dominant and recessive variants in human ROBO1 cause distinct neurodevelopmental defects through different mechanisms. Münch et al (2022 - PMID: 35227688) Biallelic Biallelic pathogenic variants in roundabout guidance receptor 1 associate with syndromic congenital anomalies of the kidney and urinary tract Woodring et al (2021 - PMID: 34193621) - Probably not relevant (VUS) Uncertain, Not Unimportant: Callosal Dysgenesis and Variants of Uncertain Significance in ROBO1 Liu et al (2020 - PMID: 31448886) Monoallelic A Novel Missense Mutation in Human Receptor Roundabout-1 (ROBO1) Gene Associated with Pituitary Stalk Interruption Syndrome. Dateki et al (2019 - PMID: 30692597) Biallelic - This individual has been incl. in the study by Munch et al A homozygous splice site ROBO1 mutation in a patient with a novel syndrome with combined pituitary hormone deficiency Rasmussen et al (2018 - PMID: 29194579) Biallelic Targeted gene sequencing and whole-exome sequencing in autopsied fetuses with prenatally diagnosed kidney anomalies Kruszka et al (2017 - PMID: 28592524) Monoallelic Loss of function in ROBO1 is associated with tetralogy of Fallot and septal defects Bashamboo et al (2017 - PMID: 28402530) Monoallelic Mutations in the Human ROBO1 Gene in Pituitary Stalk Interruption Syndrome Calloni et al (2017 - PMID: 28286008) Biallelic Compound Heterozygous Variants in ROBO1 Cause a Neurodevelopmental Disorder With Absence of Transverse Pontine Fibers and Thinning of the Anterior Commissure and Corpus Callosum Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1568 | CELF2 |
Julia Baptista gene: CELF2 was added gene: CELF2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CELF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CELF2 were set to 34107259; 33131106 Phenotypes for gene: CELF2 were set to Developmental delay; epileptic encephalopathy Mode of pathogenicity for gene: CELF2 was set to Other Review for gene: CELF2 was set to GREEN Added comment: De novo missense variants in six individuals (PMID:34107259). The variants cluster on the C‐terminus, a nuclear localization sign. Phenotypic findings include global developmental delay with moderate to severe impairment of speech and language capacities, infantile spasms, stereotypic movements and/or aggressive behaviors, and one individual was diagnosed with ASD. A previous publication (PMID: 33131106) reported five unrelated individuals (four de novo). Two missense variants, one frameshift predicted to escape NMD and one splice site variant, c.272‐1G>C were identified; these variants, except the splicing, clustered on the C‐terminus. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1561 | CCDC82 |
Konstantinos Varvagiannis gene: CCDC82 was added gene: CCDC82 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CCDC82 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC82 were set to 27457812; 28397838; 35118659; 35373332 Phenotypes for gene: CCDC82 were set to Global developmental delay; Intellectual disability; Spastic paraparesis Penetrance for gene: CCDC82 were set to Complete Review for gene: CCDC82 was set to AMBER Added comment: The phenotype of individuals with biallelic CCDC82 variants has been reported - in most cases briefly - in the following reports (each summarizing the findings of previous ones): Riazzudin et al (2017 - PMID: 27457812) in a large consanguineous pedigree from Pakistan (PKMR206) identified 4 individuals homozygous for a fs variant [NM_024725.3:c.373delG / p.(Asp125Ilefs*6)] (V3,V4,V5,V10). There was no other variant segregating with the phenotype of ID (Delayed CMS, moderate ID and speech delay probably common to all, V3,4,5 had also mild hypotonia and motor weakness). There was one unaffected sib tested (homozygous for ref. alelle). 2 further affected males (V1, V2) with similar phenotype were not tested. Harripaul et al (2018 - PMID: 28397838) reported 2 sibs with nonsyndromic ID belonging to a consanguineous family (AS17) from the Middle-East. Both were homozygous for NM_024725.3:c.535C>T / p.Arg179*. The variant was confirmed with Sanger sequencing and parents were heterozygous carriers. Two additional affected sibs were probably not tested. Yahia et al (2022 - PMID: 35118659) described 2 sibs belonging to a consanguineous family from Sudan. These presented global DD (last evaluation at 4y and 9m) and spasticity. There was a common history of infantile spasms with the elder developing GTC convulsions with spontaneous resolution. Additionaly, both presented microcephaly (<-2 and <-3SD). Exome sequencing revealed homozygosity for c.535C>T / p.Arg179* (previously reported by Harripaul et al). Sanger sequencing was used for confirmation and demonstration of carrier state of parents. Two similarly affected sibs were not available for testing. Bauer et al (2022 - PMID: 35373332) reported a 21 y.o. male born to consanguineous parents from Pakistan. Features included short stature, ID, spastic paraparesis (at the age of 3y). Gelastic seizures were suspected but not confirmed (repeated normal EEGs). WES revealed homozygosity for a fs CCDC82 variant [NM_001318736.1:c.183del / p.(Phe61Leufs*27)] with Sanger confirmation in proband and heterozygous parents. There was another hmz variant, albeit classified as VUS and not thought to fit the clinical presentation. As proposed by Bauer et al. overlapping features include spastic paraparesis, DD and dysmorphic features. As commented, CCDC82 encodes coiled-coil domain protein 82, a protein with unknown function. Consider inclusion probably with amber rating (>3 individuals/families/variants, role of the gene not known, variant studies not performed to date, animal models not discussed). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1525 | CACNA2D1 |
Konstantinos Varvagiannis gene: CACNA2D1 was added gene: CACNA2D1 was added to Intellectual disability. Sources: Literature,Other Mode of inheritance for gene: CACNA2D1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CACNA2D1 were set to 35293990; 28097321 Phenotypes for gene: CACNA2D1 were set to Abnormal muscle tone; Feeding difficulties; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of movement; Cortical visual impairment; Pain insensitivity Penetrance for gene: CACNA2D1 were set to Complete Review for gene: CACNA2D1 was set to GREEN Added comment: Consider inclusion in the current panel with green rating. Recent report of 2 unrelated individuals with DEE due to biallelic CACNA2D1 variants. Both referred to neurology/genetics for hypotonia/severe DD prior to onset of seizures. One further individual with hypotonia and severe ID (seizures not discussed, age unknown). Gene with established role, encoding α2δ-1 subunit of Cav channels. Studies for the variants support loss-of-function as the underlying effect. Eventual contribution of monoallelic variants to NDD-phenotypes discussed (and put in question) in Ref [1] below. There is currently no phenotype for CACNA2D1 in OMIM/G2P. In SysID this gene is listed among the candidates for ID, based on a previous report. CACNA2D1 is not currently included in the ID/epilepsy panels in PanelApp Australia. See also relevant review in epilepsy panel (Dr. H. Lord). Please consider also inclusion in other panels (e.g. microcephaly, corpus callosum, movement disorders, etc). [1] ---- Dahimene et al (2022 - PMID: 35293990) describe the phenotype of 2 unrelated individuals with biallelic CACNA2D1 variants. Overall, the phenotype corresponded to an early-onset DEE, characterized by abnormal muscle tone (axial hypotonia 2/2 with spasticity in extremities in 2/2), feeding difficulties (2/2), profound DD and ID (2/2), microcephaly (2/2 - approx. -2 SD in both), seizures (2/2 - 1st : onset 9m with absences and later generalized seizures, 2nd : onset 11m with hemi-clonic seizures and atypical absences). Other features included cortical visual impairment (2/2) and movement disorder (incl. choreiform movements 2/2, orofacial dyskinesia 2/2 and dystonic episodes 1/2). Brain MRI revealed corpus callosum anomalies (2/2) and cerebral atrophy (2/2). Both had echocardiography (abnormal in 1/2 - tiny PFO) and electrocardiography which was normal. Both exhibited insensibility to pain. Presentation is relevant to the current panel as first symptoms in the first 3 months with severe hypotonia and poor head control (2/2) with evaluation in neurology/genetics preceding onset of seizures in both. Trio ES was performed for both individuals and their (healthy) parents and revealed homozygosity for a fs variant in the first [NM_000722.3:c.818_822dup / p.(Ser275Asnfs*13)] and compound htz for a fs and a missense variant [c.13_23dup / p.(Leu9Alafs*5) and c.626G>A / p.(Gly209Asp)] in the second affected individual, respectively. Eventual additional variants were not discussed. Previous investigations are only provided for the 2nd and were all normal (karyotype, CMA, 15q methylation, epilepsy/neurometabolic gene panels). Voltage-gated calcium channels are heteromultimers comprising different subunits incl. an alpha-1 (α1), α2δ (alpha-2/delta), beta (β) and gamma (γ). CACNA2D1 is one of the 4 genes (CACNA2D1-4) encoding the alpha-2/delta subunit. Its product is post-translationally processed into 2 peptides, an alpha-2 and a delta subunit, held by a disulfide bond. Biallelic variants in CACNA2D2 - also encoding an alpha-2/delta subunit - cause cerebellar atrophy with seizures and variable developmental delay (# 618501). Variant studies support loss-of-function effect for the studied variants, notably by NMD for the fs one, and severe impairment of the Cav2 channel function for the missense one : - CACNA2D1 mRNA was reduced to 6-9% compared with control in fibroblasts from the 1st individual. mRNA levels for the 2nd subject were similar to control. - Quantification of the protein in whole-cell lysates from fibroblasts revealed lower α2δ levels compared to control (10-12% and 31-38% applying to the 1st and 2nd individual). - CACNA2D3 mRNA levels in fibroblasts from the 2nd patient were 2-7x higher compared to the 1st or controls suggesting a possible compensatory effect. CACNA2D2/4 mRNA levels were too low for quantification. - Gly209 lies within the gabapentin and amino-acid binding pocket and this residue is invariable in CACNA2D1/CACNA2D2 in all vertebrates and paralogs. - Transfection of tsA-201 cells with either WT or G209D HA-tagged α2δ revealed reduced cell surface expression for this missense variant (~80, for biotinylated form ~86%). - In tsA-201 cells transfected with HA-tagged Cav2.2/β1b and either α2δ-1-WT, no α2δ-1 or α2δ-1-G209D, WT resulted in increased 13x currents with no increase applying to G209D (or in absence of α2δ). Plasma membrane expression of double (GFP/HA) tagged Cav2.2 was increased upon co-expression with WT α2δ-1 which was not the case for α2δ-1-G209D. - In hippocampal neurons, double (GFP/HA)-tagged Cav2.2 could not be detected at the cell surface in the presence of α2δ-1-G209D (or no α2δ) in contrast with strong expression in presence of α2δ-1-WT. α2δ-1-G209D did not promote trafficking of Cav2.2 into hippocampal neurites, as indicated by reduced signals for both HA and GFP (for cell surface and total Cav2.2 respectively). - Co-expression of double (GFP/HA) tagged Cav2.2 with β1b and either HA-α2δ-1-WT or HA-α2δ-1-G209D in tsA-201 cells, revealed reduced complex formation of G209D with Cav2.2 Co-immunoprecipitated HA-α2δ-1-G209D had higher molecular weight compared to HA-α2δ-1-WT which suggests that α2δ-1-G209D remains as the uncleaved immature form (probably in the ER). Mouse model (several Refs in text): Mild cardiac phenotype and reduced ventricular myocyte Ca current density was observed in hmz ko mice. Similarly to the insensibility to pain human phenotype, mice had delayed neuropathic pain-related responses. Overexpression of a2δ-1 resulted in epileptiform EEG and behavioral arrest, overall supporting a critical role of α2δ-1 for mouse brain. The authors underscore that the parents of both patients (htz carriers) were healthy and review previous literature for association of monoallelic variants with epilepsy, ID and arrhythmogenic disorders (in suppl.) [Refs not here reviewed]. As for the NDD phenotype, CACNA2D1 is within a previously defined small region of overlap for 7q21.11 microdeletions associated with ID+/-epilepsy. The same study did not reveal de novo SNVs in any of the 3 contained genes within this SRO (HGF, CACNA2D1, PCLO) in 4293 patients with NDD [cited PMID: 28240412]. A frameshift variant (c.2625del) was identified in a 13-yo girl with infantile spasms and normal intelligence [cited PMID: 25877686]. A 1-bp insertion (c.659-2_659-1insT / not studied at the mRNA level) was identified in another 14-yo female with ID and epilepsy [cited PMID: 34356170]. The authors state that the phenotype (/differences) of these individuals as well as presence of pLoF CACNA2D1 variants in gnomAD [still pLI of 1] put in question pathogenicity of monoallelic variants for these phenotypes. The role of heterozygous missense variants described in relation to arrhythmogenic disorders is also discussed extensively (some downgraded to LB/VUS, others having a relatively high MAF and presence of 1-2 homozygotes in gnomAD). [2] ---- In an article cited by SysID for CACNA2D1 (2017 - PMID: 28097321), Reuter et al studied with WES and autozygosity mapping individuals with NDD belonging to consanguineous families. As in eTables1/3, a male - single affected individual born to consanguineous parents from Turkey (MR150) - was investigated by singleton ES. This individual was homozygous for a missense CACNA2D1 SNV [NM_000722.2:c.1514C>T;p.(Thr505Ile)]. Prior investigations are unavailable (although individuals with previously known P/LP CNVs were excluded). The phenotype - briefly reported - included hypotonia, severe ID, stereotypic behaviors, inguinal hernia and omphalocele. Presence of seizures was not commented on. The age of this individual was not reported. Sources: Literature, Other |
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| Intellectual disability - microarray and sequencing v3.1500 | CHKA |
Konstantinos Varvagiannis gene: CHKA was added gene: CHKA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHKA were set to 35202461 Phenotypes for gene: CHKA were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature Penetrance for gene: CHKA were set to Complete Review for gene: CHKA was set to GREEN Added comment: Klöckner (2022 - PMID: 35202461) describe the phenotype of 6 individuals (from 5 unrelated families) harboring biallelic CHKA variants. Shared features incl. abnormal muscle tone(6/6 - hypertonia or hypotonia, 3/6 each), DD/ID (6/6,severe in 4, severe/profound in 2), epilepsy (6/6 - onset: infancy - 3y2m | epileptic spasms or GS at onset), microcephaly (6/6), movement disorders (3/6 - incl. dyskinesia, rigidity, choreoatetotic movements). 2/5 individuals exhibited MRI abnormalities, notably hypomyelination. Short stature was observed in 4/6. Eventual previous genetic testing was not discussed. Exome sequencing (quattro ES for 2 sibs, trio ES for 1 individual, singleton for 3 probands) revealed biallelic CHKA variants in all affected individuals. Sanger sequencing was performed for confirmation and segregation studies. Other variants (in suppl.) were not deemed to be causative for the neurodevelopmental phenotype. 3 different missense, 1 start-loss and 1 truncating variant were identified, namely (NM_0012772.2): - c.421C>T/p.(Arg141Trp) [3 hmz subjects from 2 consanguineous families], - c.580C>T/p.Pro194Ser [1 hmz individual born to consanguineous parents], - c.2T>C/p.(Met1?) [1 hmz individual born to related parents], - c.14dup/p.(Cys6Leufs*19) in trans with c.1021T>C/p.(Phe341Leu) in 1 individual. CHKA encodes choline kinase alpha, an enzyme catalyzing the first step of phospholipid synthesis in the Kennedy pathway. The pathway is involved in de novo synthesis of glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine being the most abundant in eukaryotic membranes. CHKA with its paralog (CHKB) phosphorylates either choline or ethanolamine to phosphocholine or phosphoethanolamine respectively with conversion of ATP to ADP. As the authors comment, biallelic pathogenic variants in CHKB cause a NDD with muscular dystrophy, hypotonia, ID, microcephaly and structural mitochondrial anomalies (MIM 602541). [Prominent mitochondrial patterning was observed in a single muscle biopsy available from an individual with biallelic CHKA variants]. Other disorders of the Kennedy pathway (due to biallelic PCYT2, SELENOI, PCYT1A variants) present with overlapping features incl. variable DD/ID (no-severe), microcephaly, seizures, visual impairment etc. CHKA variants were either absent or observed once in gnomAD, affected highly conserved AAs with multiple in silico predictions in favor of a deleterious effect. In silico modeling suggests structural effects for several of the missense variants (Arg141Trp, Pro194Ser presumably affect ADP binding, Phe341 lying close to the binding site of phosphocholine). Each of the missense variants was expressed in yeast cells and W. Blot suggested expression at the expected molecular weight at comparative levels. The 3 aforementioned variants exhibited reduced catalytic activity (20%, 15%, 50% respectively). NMD is thought to underly the deleterious effect of the frameshift one (not studied). The start-loss variant is expected to result in significantly impaired expression and protein function as eventual utilization of the next possible start codon - occurring at position 123 - would remove 26% of the protein. Chka(-/-) is embryonically lethal in mice, suggesting that complete loss is not compatible with life. Reduction of choline kinase activity by 30% in heterozygous mice did not appear to result in behavioral abnormalities although this was not studied in detail (PMID cited: 18029352). Finally, screening of 1566 mouse lines identified 198 genes whose disruption yields neuroanatomical phenotypes, Chka(+/-) mice being among these (PMID cited: 31371714). There is no associated phenotype in OMIM, Gene2Phenotype or SysID. Overall this gene can be considered for inclusion in the ID and epilepsy panes with green or amber rating (>3 individuals, >3 variants, variant studies, overlapping phenotype of disorders belonging to the same pathway, etc). Consider also inclusion in the microcephaly panel (where available this seemed to be of postnatal onset). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.975 | SPEN |
Zornitza Stark edited their review of gene: SPEN: Added comment: PMID: 33596411 - 34 individuals with truncating variants in SPEN reported, most are de novo variants. - Clinical profile includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. - Authors showed haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females.; Changed rating: GREEN; Changed publications: 33057194, 33596411; Changed phenotypes: Developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI; Set current diagnostic: yes |
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| Intellectual disability - microarray and sequencing v3.963 | CDK19 |
Julia Baptista changed review comment from: De novo missense variants mapped to the kinase domain of CDK19 were described in 11 unrelated individuals (age range: 9 months to 14 years).Two recurrent changes at residues Tyr32 and Gly28 were identified. One additional case report (PMID:33568421) described a 10-month-old male patient who presented with a neurodevelopmental syndrome characterized by infantile spasms and a de novo missense variant c.92C>A (p.Thr31Asn) (also in the kinase domain). This brings the total of cases reported in the literature to 15.; to: De novo missense variants mapped to the kinase domain of CDK19 were described in 11 unrelated individuals (age range: 9 months to 14 years).Two recurrent changes at residues Tyr32 and Gly28 were identified. One additional case report (PMID:33568421) described a 10-month-old male patient who presented with a neurodevelopmental syndrome characterized by infantile spasms and a de novo missense variant c.92C>A (p.Thr31Asn) (also in the kinase domain). This brings the total of cases reported in the literature to 15. |
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| Intellectual disability - microarray and sequencing v3.360 | SETD1A | Zerin Hyder reviewed gene: SETD1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32346159; Phenotypes: Epilepsy, early-onset, with or without developmental delay, craniofacial dysmorphisms, behavioural/psychiatric abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.315 | ZMYM2 |
Konstantinos Varvagiannis gene: ZMYM2 was added gene: ZMYM2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ZMYM2 were set to 32891193 Phenotypes for gene: ZMYM2 were set to Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly Penetrance for gene: ZMYM2 were set to unknown Review for gene: ZMYM2 was set to AMBER Added comment: Heterozygous pathogenic (pLoF) ZMYM2 variants have been reported in individuals with syndromic presentation including CAKUT (in several cases) and variable neurological manifestations among extra-renal features. DD and ID were reported in some of the families described to date as summarized below. You might consider inclusion with green/amber rating in the ID panel and green in the panel for CAKUT. -- Connaughton et al (2020 - PMID: 32891193) report on 19 individuals (from 15 unrelated families) with heterozygous pathogenic ZMYM2 variants. [Article not reviewed in detail]. Affected individuals from 7 families presented with CAKUT while all of them displayed extra-renal features. Neurological manifestations were reported in 16 individuals from 14 families (data not available for 1 fam), among others hypotonia (3/14 fam), speech delay (4/14 fam), global DD (9/14 fam), ID (4/14 fam), microcephaly (4/14 fam). ASD was reported in 4 fam (4 indiv). Seizures were reported in 2 fam (2 indiv). Variable other features included cardiac defects, facial dysmorphisms, small hands and feet with dys-/hypo-plastic nails and clinodactyly. 14 pLoF variants were identified, in most cases as de novo events (8 fam). In 2 families the variant was inherited from an affected parent. Germline mosaicism occurred in 1 family. The human disease features were recapitulated in a X. tropicalis morpholino knockdown, with expression of truncating variants failing to rescue renal and craniofacial defects. Heterozygous Zmym2-deficient mice also recapitulated the features of CAKUT. ZMYM2 (previously ZNF198) encodes a nuclear zinc finger protein localizing to the nucleus (and PML nuclear body). It has previously been identified as transcriptional corepressor interacting with nuclear receptors and the LSD1-CoREST-HDAC1 complex. It has also been shown to interact with FOXP transcription factors. The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.262 | SPOP |
Arina Puzriakova changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review. Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P. At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to the different clinical manifestations.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review. Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P. At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to differences in additional clinical manifestations. |
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| Intellectual disability - microarray and sequencing v3.260 | SPOP |
Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review. Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P. At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to the different clinical manifestations. |
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| Intellectual disability - microarray and sequencing v3.201 | MORC2 |
Konstantinos Varvagiannis gene: MORC2 was added gene: MORC2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MORC2 were set to https://doi.org/10.1016/j.ajhg.2020.06.013 Phenotypes for gene: MORC2 were set to Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688 Penetrance for gene: MORC2 were set to unknown Mode of pathogenicity for gene: MORC2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: MORC2 was set to GREEN Added comment: The current review is based on a recent report by Sacoto et al (2020 - https://doi.org/10.1016/j.ajhg.2020.06.013). While several previous studies focused on the phenotype of axonal motor and senory neuropathy in individuals with heterozygous MORC2 pathogenic variants (Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688) some of them presented among others with hypotonia, muscle weakness, intellectual disability, microcephaly or hearing loss [refs provided by Sacoto et al - learning disabilities (in some patients) also listed in OMIM's clinical synopsis]. Sacoto et al present a cohort of 20 individuals having genetic testing for developmental delay or growth failure (with a single one for a diagnosis of sensorimotor neuropathy). Overlapping features included DD, ID (18/20 - mild to severe), short stature (18/20), microcephaly (15/20) and variable craniofacial dysmorphisms. The authors comment that features suggestive of neuropathy (weakness, hyporeflexia, abnormal EMG/NCS) were frequent but not the predominant complaint. EMG/NCS abnormalities were abnormal in 6 out of 10 subjects investigated in this cohort. Other findings included brain MRI abnormalities (12/18 - in 5/18 Leigh-like lesions), hearing loss (11/19) and pigmentary retinopathy in few (5). Affected subjects were found to harbor in all cases missense variants in the ATPase module of MORC2 [residues 1 to 494 - NM_001303256.1 - the module consists of an ATPase domain (aa 1-265), a transducer S5-like domain (266-494) and a coiled-coiled domain (CC1 - aa 282-361)]. Variants had occured mostly as de novo events although inheritance from a similarly affected parent was also reported. Some of them were recurring within this cohort and/or the literature eg. c.79G>A/p.Glu27Lys (x5), c.260C>T/p.Ser87Leu (x2), c.394C>T/p.Arg132Cys (4x), c.1164C>G/p.Ser388Arg (x2), c.1181A>G/p.Tyr394Cys (x3). MORC2 encodes an ATPase involved in chromatin remodeling, DNA repair and transcriptional regulation. Chromatin remodeling and epigenetic silencing by MORC2 is mediated by the HUSH (Human Silencing Hub) complex. Functional studies (MORC2-knockout HeLa cells harboring a HUSH-sensitive GFP reporter were transduced with wt or mt MORC2 followed by measurement of reporter repression) supported the deleterious effect of most variants known at the time (hyperactivation of HUSH-mediating silencing, in line with previous observations). Overall this gene can be considered for inclusion in the ID panel with green rating. Also other gene panels (e.g. for short stature, microcephaly, hearing loss, pigmentary retinopathy, etc) if it meets the respective criteria for inclusion. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.185 | DNM1L |
Arina Puzriakova changed review comment from: Associated with related phenotype in OMIM and 'probable' gene in G2P. Variants in DNM1L cause a chronic neurological disorder, which is commonly associated with neonatal lethality. Global developmental delay or cognitive impairment (mild-profound) is reported in several surviving patients: PMID: 26931468 - Two unrelated cases: A male with global developmental delay, hypotonia and status epilepticus. WES revealed a c.1048G>A, p.G350R variant, for which low-level (68%) mosaicism was detected in the maternal sample.; to: Associated with related phenotype in OMIM and 'probable' gene in G2P. Variants in DNM1L cause a chronic neurological disorder, which is commonly associated with neonatal lethality. Global developmental delay or cognitive impairment (mild-profound) is reported in several surviving patients: PMID: 26931468 - Two unrelated cases: A male with global developmental delay, hypotonia and status epilepticus. WES revealed a c.1048G>A, p.G350R variant, for which low-level (6–8%) mosaicism was detected in the maternal sample. The second patient, with diffuse hypotonia, global developmental delay, poor growth, and persistent elevation of lactate, was found to harbour a de novo DNM1L variant (c.1135G>A, p.E379K). However, another de novo change in the PDHA1 gene (c.448G>A, p.G150R) was also found, and the definitive contribution of each variant to the patients phenotype could not be ascertained. PMID: 27328748 - Compound heterozygous DNM1L variants (c.106A>G, p.Ser36Gly; c.346_347delGA, p.Glu116Lysfs*6) identified in two brothers (3 and 16-years-old) with psychomotor delay, ocular and cerebellar involvement, including mild cognitive impairment in the older brother. Some supporting functional evidence using patient fibroblasts and a yeast model. PMID: 27301544 - De novo missense variant (c.1217T>C, p.Leu406Ser) identified in a child who presented severe hypotonia, infantile spasms with suppression‐burst and a high level of lactate in CSF. Development was profoundly delayed, and he attained no developmental milestones before his death at 18 months of age. PMID: 26604000 - De novo missense substitution, (c.1085G>A; p.Gly362Asp) identified in a child with refractory epilepsy. Profound global developmental delay was reported, and at the last clinical assessment (age 7 years), he remained nonambulatory with the use of <10 monosyllabic words. PMID: 26992161 - De novo heterozygous c.1084G>A (p.Gly362Ser) variant. Developmental delay was reported from 6-months of age, and at 2-years-old he was said to not be able to utter any intelligible words. There are also reports of an identical de novo heterozygous missense variant (p.R403C) in four unrelated individuals who all experienced normal development until a sudden-onset episode of status epilepticus at the age of 4, 5, 10, and 11-years-old, respectively. Subsequently, all presented with rapid neurological regression, diffuse cerebral atrophy and substantial cognitive decline. Functional studies showed the variant confers a dominant negative effect (PMID: 27145208; 30767894; 30711678). |
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| Intellectual disability - microarray and sequencing v3.83 | SATB1 |
Eleanor Williams changed review comment from: Conference talk/abstract from ESHG 2020 - Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder - Den Hoed et al - report f26 individuals with SATB1 variants, 17 of which have missense variants and 9 have truncating variants. 21 of 26 variants (80%) were confirmed to be de novo in origin. Patients showed a broad phenotypic spectrum, including ID and/or neurodevelopmental delay, epilepsy, dental abnormalities and aspecific brain MRI findings. Additionally, patients with missense variants are more severely affected than those with truncating variants. No peer reviewed publication was found in PubMed relating to these results so recommend Amber rating for now. Sources: Other; to: Conference talk/abstract from ESHG 2020 - Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder - Den Hoed et al - report 26 individuals with SATB1 variants, 17 of which have missense variants and 9 have truncating variants. 21 of 26 variants (80%) were confirmed to be de novo in origin. Patients showed a broad phenotypic spectrum, including ID and/or neurodevelopmental delay, epilepsy, dental abnormalities and aspecific brain MRI findings. Additionally, patients with missense variants are more severely affected than those with truncating variants. No peer reviewed publication was found in PubMed relating to these results so recommend Amber rating for now. Sources: Other |
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| Intellectual disability - microarray and sequencing v3.83 | SATB1 |
Eleanor Williams gene: SATB1 was added gene: SATB1 was added to Intellectual disability. Sources: Other Mode of inheritance for gene: SATB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: SATB1 were set to intellectual disability Review for gene: SATB1 was set to AMBER Added comment: Conference talk/abstract from ESHG 2020 - Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder - Den Hoed et al - report f26 individuals with SATB1 variants, 17 of which have missense variants and 9 have truncating variants. 21 of 26 variants (80%) were confirmed to be de novo in origin. Patients showed a broad phenotypic spectrum, including ID and/or neurodevelopmental delay, epilepsy, dental abnormalities and aspecific brain MRI findings. Additionally, patients with missense variants are more severely affected than those with truncating variants. No peer reviewed publication was found in PubMed relating to these results so recommend Amber rating for now. Sources: Other |
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| Intellectual disability - microarray and sequencing v3.79 | SLC5A6 | Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene for SLC5A6-related Neurodevelopmental Disorder. At least 5 variants published in three unrelated famililies (4 cases total) with SLC5A6-related Neurodevelopmental Disorder, together with supportive functional studies (PMID 29669219; 23104561). One of the cases had mixed semiology seizures including focal dyscognitive, absence, tonic spasms and generalised convulsive seizures with electrographic features of encephalopathy with generalised and independent multifocal spike-wave discharges (PMID 31754459), another case had brain, immune, bone and intestinal dysfunction (PMID 27904971) and the third had metabolic dysfunction mimicking biotinidase deficiency (PMID 31392107). This condition could be treated with biotin supplementation and introduction of pantothenic acid supplementation (PMID 31392107). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.36 | ALG9 | Rebecca Foulger changed review comment from: PMID:26453364. AlSubhi et al., 2016 summarise 6 patients with ALG9-CDG from the literature and report 4 additional patients from a large consanguineous family. 6/10 patients had developmental disability including the index patient (IV:5), a6 year old girl with global DD, skeletal dysplasia, epilepsy, facial dysmorphisms amongst her phenotypes. The three affected cousins had similar phenotypes.; to: PMID:26453364. AlSubhi et al., 2016 summarise 6 patients with ALG9-CDG from the literature and report 4 additional patients from a large consanguineous family. 6/10 patients had developmental disability including the index patient (IV:5), a 6 year old girl with global DD, skeletal dysplasia, epilepsy, facial dysmorphisms amongst her phenotypes. The three affected cousins had similar phenotypes. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.11 | RALGAPA1 | Sarah Leigh Added comment: Comment on phenotypes: Intellectual disability;hypotonia;infantile spasms. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.11 | RALGAPA1 | Sarah Leigh Phenotypes for gene: RALGAPA1 were changed from Intellectual disability; hypotonia; infantile spasms. to Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation 618797 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.0 | RALGAPA1 |
Zornitza Stark gene: RALGAPA1 was added gene: RALGAPA1 was added to Intellectual disability. Sources: Expert list Mode of inheritance for gene: RALGAPA1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RALGAPA1 were set to 32004447 Phenotypes for gene: RALGAPA1 were set to Intellectual disability; hypotonia; infantile spasms. Review for gene: RALGAPA1 was set to GREEN gene: RALGAPA1 was marked as current diagnostic Added comment: Four unrelated individuals reported. Sources: Expert list |
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| Intellectual disability - microarray and sequencing v3.0 | MN1 |
Konstantinos Varvagiannis gene: MN1 was added gene: MN1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: MN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MN1 were set to 31834374; 31839203; 15870292 Phenotypes for gene: MN1 were set to Central hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Hearing impairment; Abnormality of facial skeleton; Craniosynostosis; Abnormality of the face; Abnormality of the cerebellum; Abnormality of the corpus callosum; Polymicrogyria Penetrance for gene: MN1 were set to Complete Review for gene: MN1 was set to GREEN Added comment: Two studies by Mak et al (2019 - PMID: 31834374 / Ref1) and Miyake et al (2019 - PMID: 31839203 / Ref2) provide sufficient evidence for heterozygous MN1 C-terminal truncating variants (predicted to escape NMD - localizing within the last nucleotides of exon 1 or in exon 2) being associated with a distinctive phenotype and DD and ID among the features. Mak et al also discuss on the phenotype of individuals with variants causing N-terminal truncation or with MN1 deletions (discussed at the end of this review). Overlapping features for C-terminal truncating variants included hypotonia, feeding difficulties, global DD and ID, hearing loss, cranial shape defects (/craniosynostosis in few), highly suggestive/distinctive facial features (eg. frontal bossing, hypertelorism, downslanting palpebral-fissures, shallow orbits, short upturned nose, low-set/posteriorly rotated/dysplastic ears, etc) and brain MRI abnormalities (eg. rhomboencephalosynapsis or cerebellar dysplasia, polymicrogyria, dysplastic CC). The majority of the affected individuals were investigated by WES/WGS with a single one tested by targeted MN1 Sanger sequencing due to highly suggestive features. Variable previous investigations incl. CMA in several, gene panel testing (Rasopathies, hearing loss, craniofacial panels, FMR1, etc) and metabolic work were normal in most. In a single case a likely pathogenic ACSL4 also explained part of the phenotype (Ref2). In the majority of these individuals, the variant had occured as a de novo event. Two sibs had inherited the truncating variant from a milder affected mosaic parent. A parental sample was not available for an additional individual. p.(Arg1295*) or NM_002430.2:c.3883C>T was a recurrent variant, seen in several individuals and in both studies. Several lines of evidence are provided for the MN1 variants and the role of the gene including: - For few individuals for whom cell lines were available, variants were shown to escape NMD by cDNA/RT-PCR/RNA-seq [Ref1 & 2]. - The gene has a high expression in fetal brain [Ref2 / fig S2] - MN1 (* 156100 - MN1 protooncogene, transcriptional regulator) has been proposed to play a role in cell proliferation and shown to act as transcription cofactor (increasing its transactivation capacity in synergy with coactivators EP300 and RAC3) [Discussion and Refs provided in Ref2]. - In vitro studies suggested increased protein stability (upon transfection of wt/mut constructs in HEK293T cells), enhanced MN1 aggregation in nuclei (when wt/mut GFP-tagged MN1 was expressed in HeLa cells), increased inhibitory effect on cell growth (MG63 cells - role of MN1 in cell proliferation discussed above) and retained transactivation activity (upon transient MN1 overexpression of wt/mt MN1 in HEK293T cells) for the variants. These seem to support a gain-of-function effect for the C-terminal truncating variants [Ref2]. - The truncating variants are proposed to raise the fraction of Intrinsically disordered regions (IDRs = regions without fixed tertiary structure) probably contributing to the above effects [Ref2]. - Expression of FLAG-tagged MN1 wt/mut MN1 followed by immunoprecipitation and mass spectrometry analysis (mCAT-Hela cells), provided evidence that MN1 is involved in transcriptional regulation: a. through binding ZBTB24 and RING1 E3 ubiquitin ligase (with mutant MN1 displaying impaired interaction with ZBTB24 and no binding to RING1) and/or b. through interaction with DNA-binding transcription factors PBX1 and PKNOX1. Proper MN1 degradation is proposed to mediate precise transcriptional regulation. [Ref2] - Transcriptome analysis in LCLs from an affected individual suggested dysregulation of genes relevant to neuronal development (eg. LAMP, ITGA, etc) and GO analysis suggested enrichment for pathways possibly linked to the observed phenotypes [Ref2]. - Discussed in both Refs1/2, homozygous Mn1-ko mice display abnormal skull bone development and die at/shortly after birth as a result of cleft palate. Heterozygous Mn1-ko mice display hypoplastic membranous bones of the cranial skeleton and cleft palate (CP), the latter with incomplete penetrance [Meester-Smoor et al 2005 - PMID: 15870292]. This is thus compatible with the cranial shape defects observed in C-terminal truncations (while CP has been reported in gene deletions, bifid uvula was reported once in C-terminal and N-terminal truncating variants, in the latter case with submucous CP). ----- The phenotype of other MN1 variants is discussed by Mak et al (Ref1) : - 3 individuals with MN1 N-terminal truncating variants (eg. Ser179*, Pro365Thrfs*120, Ser472*) presented speech delay, mild conductive hearing loss and facial features different from C-terminal truncations. None of these individuals had significant ID. - Microdeletions: One individual (#27) with 130 kb deletion harboring only MN1, presented microcephaly, DD and ID and mildly dysmorphic facial features. Deletions spanning MN1 and other genes (eg a 1.17 Mb deletion in ind. #28) and relevant cases from the literature reviewed, with mild DD/ID, variable palatal defects and/or facial dysmorphisms (distinct from the C-terminal truncating variants) among the frequent findings. [Please consider inclusion in other possibly relevant gene panels eg. for hearing loss (conductive/sensorineural in 16/20 reported by Mak et al) or craniosynostosis, etc]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1122 | TMX2 |
Konstantinos Varvagiannis edited their review of gene: TMX2: Added comment: A recent report by Vandervore, Schot et al. following the previous review (Am J Hum Genet. 2019 Nov 12 - PMID: 31735293), provides further evidence that biallelic TMX2 mutations cause malformations of cortical development, microcephaly, DD and ID and epilepsy. As a result this gene should probably be considered for inclusion in the ID/epilepsy panels with green rating. Overall, 14 affected subjects from 10 unrelated families are reported in the aforementioned study. The majority had severe DD/ID (failure to achieve milestones, absent speech/ambulation and signs of cerebral palsy) with few having a somewhat milder impairment. 12 (of the 14) presented with epilepsy (spasms, myoclonic seizures, focal seizures with/without generalization or generalized tonic-clonic seizures) with onset most often in early infancy. Upon brain MRI (in 12 individuals), 5 presented polymicrogyria, 2 others pachygyria, 4 with brain atrophy, etc. All individuals were found to harbor biallelic TMX2 mutations by exome sequencing while previous investigations in several had ruled out alternative causes (infections, metabolic or chromosomal anomalies). Missense variants, an in-frame deletion as well as pLoF (stopgain/frameshift) variants were reported. [NM_015959.3 used as ref below]. The effect of variants was supported by mRNA studies, eg. RT-qPCR/allele specific RT-qPCR. The latter proved reduced expression for a frameshift variant (c.391dup / p.Leu131Profs*6) most likely due to NMD. Total mRNA levels were also 23% lower in an individual compound htz for a missense variant and a stopgain one localized in the last exon (c.757C>T / p.Arg253*). As for the previously reported c.614G>A (p.Arg205Gln), affecting the last nucleotide of exon 6, total mRNA in skin fibroblasts from a homozygous individual was not significantly decreased. RNA-Seq however demonstrated the presence of 4 different transcripts (roughly 25% each), one representing the regular mRNA, one with intron 6 retention (also present at low levels in healthy individuals), one with loss of 11 nucleotides within exon 6 and a fourth one due to in-frame skipping of exon 6. *To the best of my understanding : Thioredoxin (TRX)-related transmembrane proteins (TMX) belong to the broader family of oxidoreductases of protein disulfide isomerase (PDI) having an important role in protein folding. Study of the data from the Allen Human Brain Atlas suggest relevant fetal expression also increasing during postnatal life. As RNA-seq was carried out for 2 individuals, GO analysis suggested that the most deregulated clusters of genes are implicated in post-translational protein modifications (as would be expected for PDIs), membranes and synapse while pathway analysis suggested that relevant categories were inhibited eg. nervous system development/function and cell growth/proliferation/survival. Upon transfection of HEK293T cells, exogenous TMX2 was shown to co-localize with calnexin (CNX) to the (ER) mitochondria-associated-membrane. Mass-spectrometry based analysis of co-immunoprecipitated proteins confirmed interaction with CNX but also other regulators of calcium homeostasis, mitochondrial membrane components and respiratory chain NADH dehydrogenase. Study of the mitochondrial activity of TMX2-deficient fibroblasts suggested reduced respiratory reserve capacity, compensated by increased glycolytic activity. TMX2 occurs in both reduced and oxidized monomeric form. It also forms (homo)dimers with the ratio of dimers/monomers increasing under conditions of oxidative stress. Variant TMX2 increased propensity to form dimers, thus mimicking increased oxidative state. This was observed under stress but also under native conditions. ---------; Changed rating: GREEN |
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| Intellectual disability - microarray and sequencing v2.1046 | TIMM50 |
Konstantinos Varvagiannis gene: TIMM50 was added gene: TIMM50 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: TIMM50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TIMM50 were set to 27573165; 30190335; 31058414; Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T) Phenotypes for gene: TIMM50 were set to 3-methylglutaconic aciduria, type IX (MIM 617698) Penetrance for gene: TIMM50 were set to Complete Review for gene: TIMM50 was set to GREEN gene: TIMM50 was marked as current diagnostic Added comment: Biallelic pathogenic TIMM50 variants cause 3-methylglutaconic aciduria, type IX (MIM 617698). At least 9 affected individuals from 5 unrelated (but often consanguineous) families of variable origin have been reported (based on a conference abstract and PMIDs : 27573165, 30190335, 31058414). TIMM50 encodes encodes a subunit of the mitochondrial presequence import machinery called the TIM23 complex. TIMM50 serves as a major receptor in the intermembrane space that binds to proteins on their way to cross the mitochondrial inner membrane (summary by Shahrour et al., 2017 and OMIM). The highly overlapping patient clinical features [seizures, DD and ID - the latter in all age-appropriate individuals (5 from 3 families - refs 2,4)], metabolic investigations (lactate elevations in many, elevated urinary 3MGA in almost all, variable mitochondrial complex deficiencies in some), additional extensive functional evidence of mitochondrial dysfunction or the similar phenotypes in other types of 3-methylglutaconic aciduria all support a role for the gene. [AUH- / CLPB- / DNAJC19- / HTRA2- / OPA3- / SERAC1-related methylglutaconic acidurias are all included as relevant disorders in the ID panel, with the respective genes rated green.] TIMM50 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx). The gene is not associated with any phenotype in G2P As a result this gene could be considered for inclusion/upgrade as green in both ID and epilepsy panels respectively. --------- [1] - Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T) reported on a patient born to consanguineous parents of South Asian ancestry with intractable epilepsy, microcephaly, DD and spastic quadriplegia. Metabolic investigations revealed increased urinary 3MGA. Two similarly affected sisters with demonstrated increase of 3MGA, were deceased following an infection. WES in the affected child, 2 unaffected sibs and the parents suggested a homozygous missense variant as the likely cause of the disorder in the proband (c.1114G>A / p.G372S - Reference not specified though the variant probably corresponds to ENST00000314349.4 and ClinVar's entry VCV000208697.1 - www.ncbi.nlm.nih.gov/clinvar/variation/208697/). [2] - Shahroor et al. (2017, PMID: 27573165) reported on 2 consanguineous families, each with 2 affected individuals. Two sibs from the 1st family (of Bedouin origin) presented with seizures (onset at 3m and 4m respectively), DD and ID with slightly elevated plasma lactate and increased urinary 3MGA upon metabolic investigations. Enzymatic activities of mitochondrial complex I-V were carried out for 1 sib and were normal also after normalization for citrate synthase. Following a SNP array, WES was carried out in affected children and their parents. Both sibs were homozygous for a missense SNV [NM_001001563.1:c.755C>T / p.Thr252Met]. Segregation studies - also in 3 unaffected sibs - supported a role for the variant. Two sibs from the 2nd family (of Muslim origin) presented with seizures (myoclonic jerks at 3m, generalized tonic movements at 2m - respectively) with DD and ID. Urinary 3MGA was elevated for both, with CSF lactate also elevated in one. WES revealed homozygosity for p.Arg217Trp (NM_001001563.1:c.649C>T) and segregation studies in parents and an unaffected sib were again compatible. The authors could not demonstrate pathogenicity of the variants in a yeast based system although - as also commented on in Ref 4 - the human TIMM50 could not rescue the yeast ΔΤim50 growth defect and global conservation between the two proteins is poor. [3] - Reyes et al. (2018, PMID: 30190335) reported on one individual with onset of infantile spasms at the age of 2m with hypsarrythmia upon EEG and psychomotor regression. Leigh-like features were noted upon brain MRI. Lactate was elevated in both plasma and CSF. Urinary 3MGA was normal. WES, Sanger confirmation and segregation studies demonstrated compound htz for 2 variants (NM_001001563:c.335C>A or p.S112* and c.569G>C or p.G190A). Functional studies demonstrated among others decrease in all components of the TIM23 complex and decreased mitochondrial membrane potential. Patient fibroblasts grown in glucose had lower levels of all complex II and IV subunits and one complex I subunit (due to the impairment in import system) with decreased mitochondrial respiration and increase in ROS production. Growth in galactose - shifting energy production toward OxPhos - caused massive cell death. The phenotype was rescued/substantially improved following complementation of patient fibroblasts with wt TIMM50. [4] - Tort et al. (2019, PMID: 31058414) reported on a boy with seizures and ID (diagnosis of West syndrome), Leigh-like MRI anomalies, cardiomyopathy with elevated plasma and CSF lactate and persistent urinary elevation of 3MGA. The proband was found to be compound heterozygous for 2 TIMM50 variants [NM_001001563.5:c.341 G>A (p.Arg114Gln) in trans with c.805 G>A (p.Gly269Ser)] following WES and Sanger confirmation/segregation studies. In patient fibroblasts TIMM50 protein levels were severely reduced upon WB although mRNA levels were similar to control. Muscle biopsy revealed decreased activity of the complexes I-IV, when normalized to the citrate synthase activity. Accumulation of lipidic material in muscle fibers was shown to be associated with mitochondria upon EM. Expression and sublocalization of mitochondria-targeted proteins were not found to be affected in patient fibroblasts. In extracts from muscle biopsy reduced protein levels of SDHA, COX4L and MTCO1 were demonstrated, in line with the disruptions in the activities of the MRC. Mitochondrial morphology and network were shown to be altered in patient fibroblasts. Patient fibroblasts showed marked reduction of max respiratory capacity. Similar reduction was noted in CRISPR/Cas9 generated TIMM50-ko HEK293T cells, but rescued upon transient transfection with a plasmid encoding for wt TIMM50. (Functional studies better summarized in the respective articles). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.977 | KIF2A |
Catherine Snow changed review comment from: Three further cases identified in the literature. PMID:27747449 (Cavallin et al 2017) detected two de novo p.Ser317Asn and p.His321Pro mutations in KIF2A in two patients with lissencephaly and microcephaly. Case 1 had DD, no epilepsy but was only 9 months old at last reporting. Case 2 had neonatal seizures and severe DD. PMID:27896282 (Tian et al 2016) report a patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous variant in KIF2A (p.Thr320Ile). Therefore upgrading rating from Amber to Green as now sufficient (>3) unrelated cases.; to: Three further cases identified in the literature. PMID:27747449 (Cavallin et al 2017) detected two de novo p.Ser317Asn and p.His321Pro mutations in KIF2A in two patients with lissencephaly and microcephaly. Case 1 had DD, no epilepsy but was only 9 months old at last reporting. Case 2 had neonatal seizures and severe DD. PMID:27896282 (Tian et al 2016) report a patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous variant in KIF2A (p.Thr320Ile). Most cases identified have epilepsy first however as one individual did not have seizures KIF2A is relevant for the ID panel. Therefore upgrading rating from Amber to Green as now sufficient (>3) unrelated cases. |
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| Intellectual disability - microarray and sequencing v2.951 | POU3F3 |
Konstantinos Varvagiannis gene: POU3F3 was added gene: POU3F3 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: POU3F3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: POU3F3 were set to https://doi.org/10.1016/j.ajhg.2019.06.007; 24550763 Phenotypes for gene: POU3F3 were set to Generalized hypotonia; Delayed speech and language development; Global developmental delay; Intellectual disability; Autistic behavior Penetrance for gene: POU3F3 were set to unknown Review for gene: POU3F3 was set to GREEN gene: POU3F3 was marked as current diagnostic Added comment: Snijders Blok et al. (2019, DOI: https://doi.org/10.1016/j.ajhg.2019.06.007) report on 19 individuals with heterozygous POU3F3 variants. Features included hypotonia in some, DD/ID (19/19) with impairment in speech and language skills, and autism-like symptoms with formal ASD diagnosis in 7(/19). Epilepsy was reported for 2 individuals. Overlapping facial features were noted among these individuals. POU3F3 encodes a member of the class III POU family of transcription factors expressed in the central nervous system (Sumiyama et al. 1996, PMID: 8703082 cited in OMIM) and as the authors comment holds a role in regulation of key processes, eg. cortical neuronal migration, upper-layer specification and production and neurogenesis (PMIDs cited: 11859196, 12130536, 22892427, 17141158). In almost all subjects (17/19) the variant had occurred as a de novo event, while one individual had inherited the variant from a similarly affected parent. In total 12 nonsense/frameshift variants, 5 missense ones as well as 1 in-frame deletion were identified following (mostly) trio exome sequencing. All variants were absent from gnomAD, with in silico predictions in favour of pathogenicity. The few missense variants and the in-frame deletion were found either in the POU-specific (NM_006236.2:c.1085G>T / p.Arg362Leu found in 2 subjects) or the POU-homeobox domain (where 2 variants affected the same residue, namely p.Arg407Gly/Leu, the other variant was p.Asn456Ser). POU3F3 is an intronless gene and as a result truncating variants are not subject to NMD. The gene appears to be intolerant to LoF variants (pLI of 0.89 in gnomAD). Western blot analysis of YFP-tagged POU3F3 variants (in HEK293 cell lysates) showed that the YFP-fusion proteins were expressed and had the expected molecular weights. For several truncating variants tested as well as the in-frame deletion, aberrant subcellular localization pattern was demonstrated although this was not the case for 4 missense variants. In vitro studies were carried out and suggested that POU3F3, as is known to be the case for POU3F2, is able to activate an intronic binding site in FOXP2. Using a luciferase assay, transcriptional activation was severely impaired for truncating variants tested, significantly lower for many missense ones with the exception of those affecting Arg407 in which case luciferase expression was either similar to wt (for Arg407Gly) or even increased in the case of Arg407Leu. As the authors comment, both loss- and gain- of function mechanisms may underly pathogenicity of variants. The ability of mutant proteins to form dimers either with wt or themselves was tested. Dimerization capacity was intact for most missense variants but was lost/decreased for truncating variants. The in-frame deletion resulted in impaired dimerization with wt, although homo-dimerization was found to be normal. --- Dheedene et al. (2014 - PMID: 24550763) had previously reported on a boy with ID. aCGH had demonstrated a de novo 360-kb deletion of 2q12.1 spanning only POU3F3 and MRPS9 the latter encoding a mitochondrial ribosomal protein (which would be most compatible with a - yet undescribed - recessive inheritance pattern / disorder). --- POU3F3 is not associated with any phenotype in OMIM/G2P. The gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc, among the principal authors of the study). --- As a result POU3F3 seems to fulfill criteria for inclusion in the current panel probably as green [DD/ID was a universal feature - severity of ID was relevant in 5/10 individuals for whom details were available, functional evidence provided] or amber. Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.938 | TRPM3 |
Konstantinos Varvagiannis changed review comment from: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences]. Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals. Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood. In all individuals the variant was found following trio exome sequencing. The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3). The Pro937Gln variant is however classified as a VUS. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date. Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc. TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain. The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3). Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals. Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7. As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases: - In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199] - Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known. ----- TRPM3 is not associated with any phenotype in OMIM or G2P. This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study). ----- As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required). [Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc]. Sources: Literature; to: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences]. Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals. Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood. In all individuals the variant was found following trio exome sequencing. The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3). The Pro937Gln variant is however also present once in gnomAD (1/251370 alleles or AF:3.98e-6) and is classified as VUS according to the ACMG criteria. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date. Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc. TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain. The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3). Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals. Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7. As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases: - In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199] - Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known. ----- TRPM3 is not associated with any phenotype in OMIM or G2P. This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study). ----- As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required). [Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.938 | TRPM3 |
Konstantinos Varvagiannis gene: TRPM3 was added gene: TRPM3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TRPM3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TRPM3 were set to doi.org/10.1038/s41431-019-0462-x Phenotypes for gene: TRPM3 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior Penetrance for gene: TRPM3 were set to unknown Mode of pathogenicity for gene: TRPM3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: TRPM3 was set to GREEN gene: TRPM3 was marked as current diagnostic Added comment: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences]. Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals. Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood. In all individuals the variant was found following trio exome sequencing. The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3). The Pro937Gln variant is however classified as a VUS. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date. Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc. TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain. The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3). Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals. Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7. As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases: - In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199] - Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known. ----- TRPM3 is not associated with any phenotype in OMIM or G2P. This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study). ----- As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required). [Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.845 | ACTL6B | Rebecca Foulger commented on gene: ACTL6B: Bell et al., 2019 (PMID:31031012) identified 11 individuals (from 10 families) with biallelic variants in ACTL6B and global developmental delay, epileptic encephalopathy, and spasticity. They also identified 10 unrelated individuals with de novo heterozygous variants with ID, developmental delay, hypotonia, Rett-like stereotypies (e.g. handwringing), and minor facial dysmorphisms: 9/10 of these individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.647 | SLC35A3 | Rebecca Foulger commented on gene: SLC35A3: Marini et al. 2017 (PMID: 28328131) provide a second case. They report a non-consanguineous Italian family with two siblings manifesting a severe EE. Both siblings exhibited infantile spasms associated with focal and tonic seizures from early infancy. In addition, both had quadriplegia, acquired microcephaly and severe ID. WGS identified novel compound het variants in SLC35A3 in both children. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.621 | NECAP1 |
Konstantinos Varvagiannis gene: NECAP1 was added gene: NECAP1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: NECAP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NECAP1 were set to 24399846; 30525121; 30626896 Phenotypes for gene: NECAP1 were set to ?Epileptic encephalopathy, early infantile 21, 615833 Penetrance for gene: NECAP1 were set to Complete Review for gene: NECAP1 was set to GREEN gene: NECAP1 was marked as current diagnostic Added comment: Biallelic pathogenic variants in NECAP1 cause ?Epileptic encephalopathy, early infantile, 21 (MIM 615833). ---- PMID: 24399846 (Alazami et al. 2014) report on 6 individuals from an multigenerational family from Saudi Arabia with biallelic NECAP1 nonsense variant. The common phenotype consisted of hypotonia, profound global developmental delay preceding the onset of intractable seizures (fragmented multifocal clonic and tonic) in early infancy. Initial workup excluded metabolic causes. 4 of these individuals were born to first cousins once removed, while 2 additional affected subjects from the broader pedigree were born to seemingly unrelated parents from the same region. All affected individuals shared a single autozygous 4.78-Mb interval on chromosome 12p. Linkage analysis confirmed involvement of this locus (LOD score : 5.0447). Exome sequencing demonstrated homozygosity for a nonsense variant (NM_015509.3:c.142C>T - p.R48*). mRNA levels in lymphoblast cell lines from affected subjects were significantly reduced when compared to controls, probably due to NMD. Necap1 was shown to be strongly expressed in the developing (E14.5) mouse brain and spinal cord, upon immunohistochemical analysis (part of the current study). NECAP1 has been previously shown to have a functional role in Clathrin-mediated encocytocis (CME), a process which plays a critical role at the site of synapsis (in synaptic vesicle recycling). ---- PMID: 30525121 (Alsahli et al. 2018) report on a 41-month-old girl with hypotonia, profound global developmental delay and onset of seizures at the age of 3 months (generalized tonic and clonic / flexor hemispasms). Initial workup was negative for an eventual metabolic origin. The girl was born to consanguineous Saudi parents and was found to harbor the p.R48* variant in the homozygous state, following trio-WES. ---- PMID: 30626896 (Mizuguchi et al. 2019) report on a 16-month-old boy, born to consanguineous parents from Malaysia. This individual presented with axial hypotonia and profound developmental delay and developed generalized tonic-clonic and clonic seizures at the (corrected) age of 3 months. EEG demonstrated a burst suppression pattern and a clinical diagnosis of Ohtahara syndrome was retained. Metabolic workup was normal. Homozygosity for a splice-site NECAP1 variant (NM_015509.3:c.301+1G>A) was demonstrated following exome sequencing. The variant was shown to result in inclusion of a 44-bp intron, resulting in frameshift and introduction of a premature termination codon (p.Gly101Aspfs*45). The level of abnormal transcript was 2-fold increased in lymphoblast cells trated with cycloheximide when compared to cells treated with DMSO, suggesting involvement of NMD. As also in PMID: 30525121, the present study suggests similarities with the DNM1-related phenotype (Epileptic encephalopathy, early infantile, 31 - #616346 - DNM1 is rated green in the ID panel) as DNM1 also participates in vesicle recycling. The authors of the present study also note that mutations in CLTC (encoding clathrin heavy chain) cause hypotonia with DD/ID with or without epilepsy (Mental retardation, autosomal dominant 56 - #617854 - CLTC is rated green in the ID panel). ---- NECAP1 is not associated with any phenotype in G2P. This gene is included in gene panels for ID offered by some diagnostic laboratories. ---- As a result this gene can be considered for inclusion in this panel as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.611 | CYFIP2 |
Konstantinos Varvagiannis gene: CYFIP2 was added gene: CYFIP2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CYFIP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CYFIP2 were set to 29534297; 29667327; 30664714; 25432536; 27524794; 12818175; 20537992 Phenotypes for gene: CYFIP2 were set to Epileptic encephalopathy, early infantile 65, 618008 Penetrance for gene: CYFIP2 were set to unknown Review for gene: CYFIP2 was set to GREEN gene: CYFIP2 was marked as current diagnostic Added comment: Heterozygous pathogenic variants in CYFIP2 cause Epileptic encephalopathy, early infantile, 65 (MIM 618008) -------------- [Apologies for any eventual mistakes esp.as for the functional evidence]: Nakashima et al. (2018 - PMID: 29534297) report on 4 unrelated individuals with early-onset epileptic encephalopathy due to de novo missense CYFIP2 variants. The phenotype consisted of early-onset intractable seizures (diagnosis of West syndrome in 2, Ohtahara syndrome in further individuals) with hypotonia (3/4), DD/ID (4/4) and microcephaly (3/4). All variants affected Arg87 residue (NM_001037333.2:c.259C>T or p.Arg87Cys in 2 individuals, the 2 other subjects harbored Arg87Leu and Arg87Pro respectively). CYFIP2 encodes the cytoplasmic FMRP interacting protein 2. CYFIP2 (similar to CYFIP1) is a component of the WAVE regulatory complex (WRC) which has been shown to play a role in actin remodeling, axon elongation, dendritic morphogenesis and synaptic plasticity (several PMIDs cited). In the inactive state of the WRC complex, CYFIP2 binds to the VCA domain of WAVE. GTP-bound Rac1 (GTPase) leads to release of the VCA domain from CYFIP2 which allows binding of this domain to the Arp2/3 complex (active WRC state) and in turn stimulates actin polymerization and lamellipodia formation. Using lymphoblastoid cell lines from affected individuals and healthy controls and CYFIP2 expression was evaluated by Western Blot and was found to be similar between the 2 groups. Additional studies suggested weaker binding of the WAVE1 VCA domain to mutant CYFIP2 compared to WT CYFIP2 (upon transfection of HEK293T cells). This could possibly favor activation of WRC (/the WAVE signalling pathway). As a result a gain-of-function effect on the WAVE signalling pathway is suggested as a possible mechanism. Using B16F1 mouse melanoma cells lamellipodia formation (process in which CYFIP2 has previously been implicated) was not shown to be impaired in the case of mutant CYFIP2. However aberrant accumulation of F-actin (and co-localization with mutant CYFIP2) was observed in the present study. Only large 5q deletions spanning CYFIP2 (and several other genes) have been described to date. Cyfip2 heterozygous knockout in mice results in abnormal behavior and memory loss. WAVE activity was enhanced (despite reduced WAVE protein production). Homozygous Cyfip2 loss is lethal (PMIDs cited by the authors: 25432536, 27524794). Impaired axonal growth, guidance and branching is noted in Drosophila mutants (CYFIP1/2 ortholog) (PMID cited: 12818175). The authors comment that Cyfip2 (nev) mutant zebrafish show a similar phenotype to mutant flies (PMID cited: 20537992). -------------- Peng et al. (2018 - PMID: 29667327) in a study of 56 Chinese families with West Syndrome (epileptic/infantile spasms, hypsarrhytmia and ID) identified 1 individual with the Arg87Cys CYFIP2 variant as a de novo occurrence. -------------- Zweier et al. (2019 - DDD study among the co-authors - PMID: 30664714) report on 12 unrelated subjects with heterozygous pathogenic de novo CYFIP2 variants. The common phenotype consisted of tone abnormalities (12/12), DD/ID (12/12) and seizures (12/12 though a single individual had experienced a single episode of febrile seizure). Absolute or relative microcephaly and/or additional features were also noted in several individuals. 7 missense variants (4 occurrences of the Arg87Cys variant) as well as splice variant (shown to lead to exon skipping) are reported, as de novo events in these individuals. The splice variant was expected to escape NMD producing a truncating protein. Although the variants are distantly located in the primary structure, spatial clustering (in the tertiary structure) is suggested by in silico modelling (all in proximity at the CYFIP2-WAVE1 interface). CYFIP2 appears to be intolerant to both missense and LoF variants (Z-score of 6.15 and pLI of 1 respectively in ExAC). The authors comment that haploinsufficiency as a mechanism is rather unlikely given the absence of small CNVs or variants predicted to lead to NMD. Again, a gain-of-function effect of these variants on WAVE activation (partial-loss-of function in terms of WRC stabilization and/or conformation of the VCA region in the inactive state) is proposed. -------------- CYFIP2 is not associated with any phenotype in G2P. The gene is included in gene panels for intellectual disability offered by some diagnostic laboratories (eg. participants in these studies). -------------- As a result this gene could be considered for inclusion in this panel as green. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.595 | NUS1 |
Konstantinos Varvagiannis gene: NUS1 was added gene: NUS1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: NUS1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: NUS1 were set to 25066056; 29100083; 24824130; 30348779 Phenotypes for gene: NUS1 were set to #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function Penetrance for gene: NUS1 were set to unknown Review for gene: NUS1 was set to AMBER gene: NUS1 was marked as current diagnostic Added comment: Mutations in NUS1 have been implicated in recessive as well as dominant forms of ID (1 and 3 unrelated individuals respectively). The latter individuals presented with a developmental and epileptic encephalopathy with ID. At least 2 of these individuals had tremor and other movement disorders. A recent study proposes that NUS1 variants contribute to Parkinson's disease (1 individual with de novo variant affecting the canonical splice site, 26 additional individuals with missense variants - for which segregation studies where not however performed). ID is not commented on for these individuals. NUS1 is included in the DD panel of G2P, associated with "Epilepsy and intellectual disability". (Monoallelic LoF variants / Disease confidence : probable). This gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc). Associated phenotypes in OMIM and others discussed in the literature are summarized below (to my understanding). As a result, NUS1 can be considered for inclusion in the ID panel probably as amber. -------- Recessive - [MIM #617082 - ?Congenital disorder of glycosylation, type 1aa] : Park et al. (2014 - PMID: 25066056) report on an individual homozygous for a NUS1 missense variant (R290H) and suggest that biallelic variants cause a congenital disorder of glycosylation. The authors based in studies in yeast, mice and man provide evidence that NUS1 encodes the Nogo-B receptor (NgBR), a subunit of cis-prenyltransferase (cis-PTase), important for its activation. cis-PTase catalyzes one of the reactions for dolichol biosynthesis. Dolichol, in turn, is a carrier of glycans for N-linked glycosylation, O-mannosylation and GPI anchor biosynthesis. Genetic defects in the dolichol biosynthetic pathway have been linked to other forms of CDG and/or other recessive or dominant neurodevelopmental disorders (eg. SRD5A3- and DHDDS-related disorders). Similarities are provided at the cellular level between different organisms. Heterozygous knockout mice appear normal. Homozygosity is associated with embryonic lethality before E6.5. Conditional knockout in mouse embryonic fibroblasts led to accumulation of free cholesterol, decreased cis-PTase activity, and mannose incorporation in protein (the first & third rescued by transduction with lentiviral human NgBR). In patient fibroblasts protein levels appeared similar to controls. Interaction with Nogo-B (and hCIT - the product of DHDDS) was not affected. As in mice, accumulation of free cholesterol was observed in cells, with decreased cis-PTase activity and mannose incorporation. LAMP-1 and ICAM-1 were hypoglycosylated in patient fibroblasts. Altered dolichol profiles in serum and urine were observed in carriers of the NUS1 variant, similarly to what described in individuals with DHDDS LoF variants. ---------- Dominant - [MIM #617831 - Mental retardation, autosomal dominant 55, with seizures]. Hamdan et al. (2017 - PMID: 29100083) report on 3 unrelated individuals with developmental and epileptic encephalopathy (onset: 10m - 2.5y) and ID. Two individuals harbored de novo LoF variants while a third subject had a deletion of exon 2. Movement disorders were noted in all 3 and included tremor (2 subjects) or ataxia (1 additional subject). The authors cite a previous study on 6q22.1 deletions the critical region of which encompassed only NUS1 and the promoter of SLC35F1 (Szafranski et al. - PMID: 24824130). Haploinsufficiency is discussed as a possible mechanism (pLI of 0.87). A more severe phenotype due to dramatic reduction of NUS1 activity is proposed for the previously reported patient with CDG. ---------- Other: Guo et al. (2018 - PMID: 30348779) suggest that NUS1 pathogenic variants contribute to Parkinson's disease. By performing WES in 39 individuals with early onset Parkinson's disease and their unaffected patients (and sibs) the authors identified 1 individual with de novo insertion affecting a NUS1 canonical splice site. RT-PCR demonstrated increased mRNA levels compared with controls. Skipping of 91 bp of exon 3 was demonstrated. Study in 2 large sporadic PD-patient (N=1852+3237)/control cohorts (N=1565+2858) suggested association between NUS1 non-synonymous variants and PD (P=1.01e-5, OR:11.3). Other genetic causes of PD were excluded in 26 additional individuals with NUS1 missense variants. Phenotypes of all 27 individuals are provided in Dataset_S04. NUS1 has been found to be differentially expressed in PD mouse models. RNAi-mediated knockdown of Tango14 (the Drosophila NUS1) resulted in impaired climbing activity, reduction in brain dopamine levels and abnormal apoptotic signals in brain. Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.588 | MAPK8IP3 |
Konstantinos Varvagiannis gene: MAPK8IP3 was added gene: MAPK8IP3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: MAPK8IP3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: MAPK8IP3 were set to 25363768; 28213671; 28135719 Penetrance for gene: MAPK8IP3 were set to unknown Review for gene: MAPK8IP3 was set to GREEN Added comment: Platzer et al. (doi.org/10.1016/j.ajhg.2018.12.008) report on 13 unrelated individuals with de novo pathogenic variants in MAPK8IP3. The phenotype consisted - among others - of DD with ID (13/13) as well as variable brain anomalies (incl. cerebral or cerebellar atrophy, corpus callosum anomalies, perisylvian polymicrogyria, etc). Microcephaly, seizures, ataxia, ASD were features seen in fewer individuals. The variants reported included 2 nonsense, 1 frameshift as well as 6 missense mutations (3 missense variants were found - each - in 2 or more individuals). All three LoF variants were located in the first exon. (mRNA levels were not studied for these variants although NMD is presumed). The brain anomalies were more consistent for missense variants. MAPK8IP3 appears intolerant to LoF variants (pLI of 1) with constraint also for missense variants (Z-score of 4.06). In silico structural modeling was possible for 4 missense variants based on available crystal structures and different mechanisms were presumed (disruption of contacts between Leu444 of adjacent subunits, altered interaction between proximal residues at positions 461 and 466, or disruption of protein protein interactions). The C.elegans MAPK8IP3 ortholog is encoded by the unc-16 gene. Impaired clearance and accumulation of organelles (incl. lysosomes) in axons is observed in unc-16 mutants (recessive phenotype). For 6 variants, also conserved in C.elegans, mutants were engineered using CRISPR genome editing. The observed mutant phenotypes (increased axonal lysosomal density compared to controls for 2 variants, sluggish locomotion with lower swimming cycle rate for 1 nonsense and 4 missense variants) were rescued upon CRISPR reverse engineering of each mutant allele back to its wild-type sequence. The authors cite 3 previous studies, in which individuals investigated for neurodevelopmental disorders where found to harbor de novo MAPK8IP3 variants, namely: - PMID 25363768 (Iossifov et al.) : p.Tyr94Cys [ASD without ID] - PMID 28213671 (Berger et al.) : p.Glu461Gly [Smith-Magenis-like phenotype) - PMID 28135719 (DDD study) p.Arg1146Cys [This variant was found in 3 individuals in the study by Platzer et al.] ------------ A few additional individuals with neurodevelopmental disorders appear in the denovo-db after filtering for coding variants: http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=MAPK8IP3 ------------ NM_015133.4:c.111C>G (p.Tyr37Ter) has been submitted in ClinVar by the Undiagnosed Diseases Network (NIH) as likely pathogenic, associated with MAPK8IP3-related disorder (hypotonia, DD, EEG anomalies among the phenotypes). It is not clear whether this subject corresponds to individual #3 reported by the previous study (possibly not the case). ------------ MAPK8IP3 is not associated with any phenotype in OMIM, nor in G2P. This gene is not commonly included in gene panels for ID. ------------ As a result, MAPK8IP3 can be considered for inclusion in this panel as green (rather than amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.588 | PPP2CA |
Konstantinos Varvagiannis gene: PPP2CA was added gene: PPP2CA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PPP2CA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PPP2CA were set to 29274472; 30030003 Phenotypes for gene: PPP2CA were set to Feeding difficulties; Muscular hypotonia; Global developmental delay; Intellectual disability; Language impairment; Seizures; Abnormality of nervous system morphology Penetrance for gene: PPP2CA were set to unknown Review for gene: PPP2CA was set to GREEN Added comment: Reynhout et al. (doi.org/10.1016/j.ajhg.2018.12.002 - PMID not available) report on 16 individuals with heterozygous pathogenic PPP2CA variants. Frequent features included feeding difficulties, hypotonia, developmental delay (16/16) with intellectual disability (probably 15/16 - a single individual developped cognitive dysfunction following a psychotic episode), language impairment, behavioral problems, seizures (10/16), brain abnormalities and variable other features. The variants reported included 3 nonsense mutations, 1 frameshift, 1 duplication of one amino acid, 9 missense variants (of which one was observed twice and 2 affected Asp223) as well as a partial gene deletion (spanning also CDKL3). Various mechanisms seemed to explain the effect of the different variants - among others - haploinsufficiency for some or a dominant negative effect for others, etc. Type 2A protein phosphatases (PP2As) comprise 3 subunits, a catalytic C-type subunit (PPP2CA encodes the Cα subunit), a scaffolding A-type subunit as well as a regulatory B-type subunit important for their function. Impairment of PP2A-B56δ (encoded by PPP2R5D) binding/functionality was suggested for most of the variants. Similar dysfunction has been observed - among others - upon loss of one functional allele of PPP2R1A. The effect of 2 variants affecting Asp223 (Asp223Val and Asp233His) was unclear as they largely behaved similar to wild-type in various functional assays. The authors argue that contribution of mutations in other genes could not be ruled out for the individuals harboring these variants, as could also be the case for the subject with disruption of (also) CDKL3. The authors note overlapping phenotype with PPP2R1A and PPP2R5D-related ID (MIM 616362 and 616355 respectively - genes rated green in this panel). Brain-specific Ppp2ca knockout in mice (PMID: 29274472) resulted in morphological and behavioral abnormalities partly overlapping with features observed in individuals with PPP2CA mutations. However mice heterozygous for null mutations have not been phenotypically examined (PMID: 30030003). --------- PPP2CA is not associated with any phenotype in OMIM, nor in G2P. This gene is not commonly included in gene panels for ID offered by diagnostic laboratories. --------- As a result, PPP2CA can be considered for inclusion in this panel as green. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.588 | CTNNA2 |
Konstantinos Varvagiannis gene: CTNNA2 was added gene: CTNNA2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CTNNA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CTNNA2 were set to 30013181 Phenotypes for gene: CTNNA2 were set to Cortical dysplasia, complex, with other brain malformations 9 (MIM 618174) Penetrance for gene: CTNNA2 were set to Complete Review for gene: CTNNA2 was set to AMBER Added comment: Biallelic loss-of-function mutations in CTNNA2 cause cortical dysplasia, complex, with other brain malformations 9 (MIM 618174). ------- Schaffer et al. (PMID: 30013181) report on 7 individuals from 3 unrelated consanguineous families. All individuals presented with profoundly impaired motor and cognitive development (severe ID in 6/7 for whom this information was available, all 6 from 2 families - a further individual from the 3rd family was non-ambulatory with absent speech at the age of 28 months), with acquired microcephaly and intractable seizures (7/7 - onset: 6m-3y - atonic/myoclonic/infantile spasms). Pachygyria without posterior-anterior gradient or focal dysplasias was common to all. CTNNA2 encodes αN-catenin. It is expressed in human fetal brain, mainly in regions expressing migration markers DCX and TUJ1. Reduced migration was shown for iPSC-derived neural progenitor cells from an affected individual, compared to controls. The protein contains a putative actin-binding domain (ABD) at its C terminus. Several lines of evidence are provided that this domain is critical for the process of neuronal migration. ------- CTNNA2 is included in the DD panel of G2P associated with disordered cortical neuronal migration (Disease confidence: probable / ID and seizures among the phenotypes assigned to this entry). This gene is not commonly included in gene panels for intellectual disability. ------- As a result CTNNA2 could be considered for inclusion in this panel as amber or possibly green. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.584 | FUK |
Konstantinos Varvagiannis gene: FUK was added gene: FUK was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FUK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FUK were set to 30503518 Phenotypes for gene: FUK were set to Feeding difficulties; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures Penetrance for gene: FUK were set to Complete Review for gene: FUK was set to AMBER Added comment: Ng et al. (PMID: 30503518) report on 2 unrelated individuals with biallelic pathogenic variants in FUK. The common features consisted of feeding difficulties, hypotonia, global developmental delay with severe intellectual disability, seizures as well as visual impairment. The first patient was compound heterozygous for 2 missense variants (Ser223Pro and Arg683Cys) while the second - born to consanguineous parents - was homozygous for Lys994Gln. Significant reduction in the FUK protein amount was demonstrated upon Western blot for the first individual for whom fibroblast and lymphoblast cell lines were available. Fucokinase (FUK) is an enzyme of the fucose salvage pathway, one of the mechanisms (the other and main contributor being the de novo pathway) for synthesis of GDP-fucose. GDP-fucose is a donor substrate for fucosylation, a form of glycosylation. Significant decrease of fucokinase activity was shown for this individual when compared to controls. Cell lines from the second individual were not available for expression/functional studies. Overall the authors suggest loss-of-function variants cause a congenital disorder of glycosylation with ID and seizures. There are no further cases published in the literature. FUK is not associated with any phenotype in OMIM nor in G2P. As a result this gene can be considered for inclusion in this panel as amber. [You might consider inclusion of this gene also in the CDG gene panel]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.579 | PUS3 |
Konstantinos Varvagiannis gene: PUS3 was added gene: PUS3 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: PUS3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PUS3 were set to 27055666; 30308082 Phenotypes for gene: PUS3 were set to Global developmental delay; Intellectual disability; Microcephaly Penetrance for gene: PUS3 were set to Complete Review for gene: PUS3 was set to AMBER gene: PUS3 was marked as current diagnostic Added comment: PUS3 (Pseudouridylate synthase 3) is proposed as a gene related to ID in a recent publication on PUS7. Biallelic mutations in this gene are associated in OMIM with ?Mental retardation, autosomal recessive 55 (MIM 617051). PMID: 27055666 reports on 3 sisters from a consanguineous Saudi Arabian family with failure to thrive, DD/ID, microcephaly and some common (coarse) facial features. These individuals were homozygous for a stopgain mutation in the last exon of the gene. Pseudouridylation appeared to be defective (as has also been the case with other genes related to ID, eg. PUS7). PMID: 30308082 describes 1 individual born to consanguineous Palestinian parents, homozygous for a further LoF variant. Despite the localisation of this variant (again in the last exon of the gene) qPCR analyses were suggestive of degradation of the abnormal transcript possibly by NMD. The phenotype consisted of DD/ID and microcephaly. In a further publication (http://dx.doi.org/10.7124/bc.0008D6) Gulkovskyi et al. report on 2 siblings with ID, born to non-consanguineous Ukranian parents. Pathogenicity of the variant is disputed. [NM_031307.4:c.212A>G or p.(Tyr71Cys) is found in an apparent homozygous state in the sibs but was only found in their father. De novo occurence in the maternal allele is proposed although the possibility of microdeletion missed by aCGH or other plausible mechanisms are not considered. This variant has maximum pathogenicity scores in silico (not discussed) and has an allele frequency of 0.00006717 in gnomAD. The authors did not perform studies of pseudouridylation but examined for the presence of hypoproteinemia, observed in some disorders affecting this process). PUS3 is not associated with any phenotype in G2P but is associated with disease in OMIM. The gene is included in gene panels for ID offered by various diagnostic laboratories (including Radboudumc). PUS1 is included in the current panel as green and PUS7 has been suggested for inclusion. As a result, these gene can be considered for inclusion as amber (2 families) or green (given the supportive functional studies and/or the proposed role for the gene). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.562 | CAD |
Konstantinos Varvagiannis gene: CAD was added gene: CAD was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CAD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CAD were set to 25678555; 28007989 Phenotypes for gene: CAD were set to Epileptic encephalopathy, early infantile, 50 - MIM 616457 Penetrance for gene: CAD were set to Complete Review for gene: CAD was set to AMBER gene: CAD was marked as current diagnostic Added comment: Biallelic pathogenic variants in CAD cause Epileptic encephalopathy, early infantile, 50 - MIM 616457. Overall 5 individuals from 4 unrelated families have been reported in detail in PMIDs 25678555 and 28007989 (table 1 in this article provides a summary). The phenotype consisted of developmental delay which preceded the onset of seizures (6 months to 2 years) and hematologic anomalies (anemia and anisopoikilocytosis). The patients presented developmental stagnation/regression, which in most cases occurred several months following the seizure onset. CAD is a tri-functional protein catalyzing the first 3 steps of the de novo pyrimidine biosynthesis. In total, 5 variants have been reported (2 missense, 1 nonsense and 2 splice-site SNVs) with functional studies (cDNA, metabolites) supporting pathogenicity and disruption of this pathway. CAD mutations have previously been studied in other model organisms. Mutations in enzymes catalyzing downstream steps of the same pathway are associated with other syndromes. The disorder appears to be amenable to dietary intervention (uridine supplementation). CAD is included in gene panels for intellectual disability offered by different diagnostic laboratories. As a result, this gene can be considered for inclusion in the ID panel as amber or green. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.468 | SMS | Louise Daugherty Source Victorian Clinical Genetics Services was added to SMS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.443 | ISCA-37431-Gain |
Louise Daugherty Region: ISCA-37431-Gain was added Region: ISCA-37431-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37431-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37431-Gain were set to 25205021; 22241097; 18183042 Phenotypes for Region: ISCA-37431-Gain were set to early onset of baldness (15 years old), dental enamel hypoplasia and minor facial dysmorphism; Chromosome 17q11.2 deletion syndrome, 1.4Mb; DD/ID, facial dysmorphisms, and seizures |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37430-Loss |
Louise Daugherty Region: ISCA-37430-Loss was added Region: ISCA-37430-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37430-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for Region: ISCA-37430-Loss were set to microcephaly, dysgenesis of the corpus callosum, and cerebellar atrophy, as well as neurobehavioral disorders, including delayed development, mental retardation, and attention deficit-hyperactivity disorder. Patients with duplications of YWHAE tended to have macrosomia, facial dysmorphism, and mild developmental delay; growth restriction, craniofacial dysmorphisms, structural abnormalities of brain and cognitive impairment; Chromosome 17p13.3 duplication syndrome; prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip, thin vermilion border, and small jaw; Characteristic facies, pre- and post-natal growth retardation; 247200; classic lissencephaly (pachygyria, incomplete or absent gyration of the cerebrum), microcephaly, wrinkled skin over the glabella and frontal suture, prominent occiput, narrow forehead, downward slanting palpebral fissures, small nose and chin, cardiac malformations, hypoplastic male extrenal genitalia, growth retardation, and mental deficiency with seizures and EEG abnormalities; Miller-Dieker lissencephaly syndrome |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37411-Loss |
Louise Daugherty Region: ISCA-37411-Loss was added Region: ISCA-37411-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37411-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37411-Loss were set to 19289393; 19136953; 18278044 Phenotypes for Region: ISCA-37411-Loss were set to PMID: 19289393 incomplete penetrance for developmental delay, mental retardation, or borderline IQ in most and autistic spectrum disorder (6/14), speech delay, aggressiveness, attention deficit hyperactivity disorder, and other behavioural problems; 612001; PMID: 18278044 mental retardation, epilepsy and variable facial and digital dysmorphisms; PMID: 19136953 idiopathic generalized epilepsy without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37420-Loss |
Louise Daugherty Region: ISCA-37420-Loss was added Region: ISCA-37420-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37420-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37420-Loss were set to 25217958; 18628315 Phenotypes for Region: ISCA-37420-Loss were set to PMID: 18628315 developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour, other clinically important features include epilepsy, heart defects and kidney/urologic anomalies; 610443; PMID: 25217958; Koolen-De Vries syndrome 610443 |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37424-Loss |
Louise Daugherty Region: ISCA-37424-Loss was added Region: ISCA-37424-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37424-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37424-Loss were set to 25217958; 20345475; 21248748; 24550761 Phenotypes for Region: ISCA-37424-Loss were set to PMID 20345475 macrocephaly, hypertelorism, and arachnodactyly, and neurodevelopmental delay that includes failure to thrive, hypotonia, and feeding difficulties in the neonatal period, and receptive and expressive language delay with global neurodevelopmental delay after the neonatal period. PMID: 21248748 developmental delay, mainly affecting speech. In addition, macrocephaly, mild facial dysmorphisms, cerebellar anomalies, cardiac defects and congenital breast aplasia; PMID: 25217958 none specified; PMID: 24550761 age-appropriate language development evaluated by a standardized test at an age of 2 years and 3 months. The boy was born with a cleft palate - a feature not present in any of the patients described before, phenotype of patients with an LCR3/4-flanked 10q22.3q23.2 deletion can be rather variable |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37478-Gain |
Louise Daugherty Region: ISCA-37478-Gain was added Region: ISCA-37478-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37478-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37478-Gain were set to 18374305; 16840569; 9106540 Phenotypes for Region: ISCA-37478-Gain were set to hypotonia and motor delays, intellectual disability, autism spectrum disorder (ASD), and epilepsy including infantile spasms, 608636; chromosome 15q11-q13 duplication syndrome; autism, mental retardation, ataxia, seizures, developmental delays, and behavioral problems |
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